KR20170005868A - Novel compounds useful as s100-inhibitors - Google Patents

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the compound. The present compounds are inhibitors that interfere with the interaction between S100A9 and its interaction partners, such as RAGE, TLR4 and EMMPRIN, and are therefore useful for the treatment of disorders such as cancer, autoimmune disorders, inflammatory disorders and neurodegenerative disorders.

Description

S100 - New compounds useful as inhibitors {NOVEL COMPOUNDS USEFUL AS S100-INHIBITORS}

The present invention relates to novel N- (2-oxo-3- (trifluoromethyl) -2,3-dihydro-1H-benzo [d] imidazo [ Derivatives, pharmaceutical compositions of these derivatives and their use as medicaments. More particularly, the present invention relates to the aforementioned derivatives for use in the treatment of cancer, autoimmune disorders, inflammatory disorders and neurodegenerative disorders.

S100A9 belongs to the S100-family of calcium-binding proteins and has been recognized as an attractive new therapeutic target for the treatment of, for example, autoimmune, inflammatory diseases, neurodegenerative diseases and cancer. Other S100 proteins play a different role in a wide variety of biological processes and are linked to a number of diseases, including cancer, cardiomyopathy, atherosclerosis, Alzheimer's disease and inflammatory diseases. 21 human genes, including S100A9, are located in the chromosome 1q21 region, a region that is frequently transformed in tumors (Marenholz et al ., 2004). Interestingly, despite the varying primary sequence among family members, the tertiary structure of several proteins is very similar.

S100A9 is often expressed together with another member of the S100 protein family, S100A8, which is highly expressed in myeloid cells such as neutrophils and mononuclear cells as well as in other cells or tissues (Srikrishna 2012). These form non-covalent isotopic and heterotypic complexes that can be specifically released in response to cell activation (Foell et al., 2007, Ryckman et al., 2003). S100A9 can be functionally described as a damage-associated molecular pattern (DAMP) molecule that is released in tissues and induces signal transduction by interaction with receptors such as RAGE and TLR4 (Foell et al., 2007, As will be described later). As in the case of many other DAMP molecules, S100A9 also binds to, for example, the cytoskeleton in addition to extracellular function, thereby affecting rearrangement of the cytoskeleton, thereby acting on cell migration, thereby also performing intracellular function (Srikrishna 2012).

The pro-inflammatory role of S100A9 is enhanced by elevated levels of S100A9 in the serum in inflammatory diseases and by high levels of S100A9 in the area of local inflammation such as rheumatoid arthritis patients (Foell & Roth, 2004) Backed. In addition, S100A9 was found at high levels in several types of cancer, and high expression levels have been demonstrated to correlate with poor tumor differentiation in some of these cancer types (Arai et al. , 2001). Increased levels of S100A9 in cancer as well as pathological conditions of chronic inflammation demonstrate the potential role of S100A9 in inflammatory carcinogenesis.

The role of S100A9 in associating the immune system with cancer is also demonstrated in bone marrow-derived inhibitory cells (MDSC), a mixture of immature myeloid cells that inhibit activation of T- and NK-cells and promote angiogenesis and tumor growth S100A8 and S100A9 are highly expressed and are also supported by studies showing that they are important for the function of such cells (Cheng et al. , 2008, Sinha et al. , 2008, Wang et al ., 2013). The balance between these processes can be favorably altered in anti-angiogenic and immunosuppressed environments by inhibiting the accumulation of tumor-invasive MDSCs by S100A9-regulation, thereby inhibiting tumor progression. In addition, data suggesting the role of S100A9 in translocating inflammatory and tumor cells to the metastatic site have been suggested (Hiratsuka et al. , 2006, Acharyya et al., 2012, Hibino et al., 2013). That is, blocking function of S100A9 can provide a new way of preventing the transition.

Although a number of potential biological functions of S100A9 have been proposed, the precise role of S100A9 in inflammation, cancer, and other diseases has not yet been elucidated. Members belonging to the S100 protein family are around - has been reported to interact with the inflammatory molecule RAGE bar, through experiments Ca ^{2 +,} and Zn ^{2 +,} this S100A9 in the conditions that exist in the physiological levels of the most powerful among the S100 family RAGE binding factor (Bjork et al. 2009). Through these experiments, it has also been demonstrated that S100A9 interacts with toll-like receptor 4 (TLR4). As in the S100A9-RAGE interaction, S100A9-TLR4 interactions, it is possible that it is strictly dependent on the physiological level of Ca ^{+ 2} and Zn ^{+ 2} present. Another receptor of S100A9, which may be important in cancer, is EMMPRIN (CD147), which is expressed on various types of cells, and the S100A9-EMMPRIN interaction has been shown to be involved in melanoma metastasis (Hibino et al. 2013).

The S100A8 and S100A9 proteins have been described as cytoplasmic proteins that are released from the myeloid cells, mainly when activated. In general, it is believed that the S100 protein must be released into the extracellular space for the main biological function associated with inflammation. In this model, extracellular S100A9 binds to, for example, the pro-inflammatory receptors RAGE and TLR4, leading to an inflammatory response. This is supported by experiments in which S100A8 / A9 induces production of TNFα through TLR4 in human peripheral blood mononuclear cells (Vogl et al. 2007). In addition, S100A9 has been shown to exert direct proliferative activity on tumor cells via RAGE signaling in the form of a complex with S100A8 (Ghavami et al. , 2008). In addition, S100A9 is also present in membrane-bound form on mononuclear cells (Bhardwaj et al., 1992). Membrane-bound S100A9 opens the possibility of cell-cell or cell-ECM signaling involving S100A9.

Data accumulated so far suggest that S100A9 plays an important role in inflammation, cancer proliferation, cancer metastasis and their connections. New compounds that inhibit the activity of S100A9 and disturb the microenvironment of the tumor in this process will be attractive for treating various types of cancer.

In addition to cancer, inflammation and autoimmunity, S100A9 has a strong association with neurodegenerative diseases. S100A9 is upregulated in the brain both in patients with Alzheimer's disease (AD) and in mouse disease models (Shepherd et al., 2006, Ha et al., 2010). In addition, in the mouse AD model, knockdown or deficit of S100A9 inhibits brain cognitive decline and plaque burden (Ha et al., 2010, Chang et al., 2012). In addition, the role of RAGE in the AD model has been demonstrated, with inhibition of RAGE mitigating disease in the mouse AD model (Deane et al., 2013). Inhibition of S100A9 and its interaction suggests a novel and promising approach to therapeutic intervention in AD and other neurodegenerative diseases.

International Application No. PCT / US2007 / 020982 (publication number WO2008042282) International Application No. PCT / US2009 / 050797 (publication number WO2010009290) International Application No. PCT / US2008 / 003935 (publication number WO2008118454)

  Acharyya S et al., A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 2012, 150 (1), 165-7   Arai K et al., S100A8 and S100A9 overexpression associated with poor pathological parameters in invasive ductal carcinoma of the breast. Curr Cancer Drug Targets 2008, 8 (4): 243-52   Attia M, et al. (1966). Cancer Res., 26: 1787-1800   Bhardwaj RS et al., The calcium-binding proteins MRP8 and MRP14 form a membrane-associated heterodimer in a subset of monocytes / macrophages present in acute but absent in chronic inflammatory lesions. Eur J Immunol 1992, 22: 1891-97   Bjork P et al., Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides. PLoS Biol. 2009, 7 (4): e97   [4,7] phenantrolines and 1-oxo-1,4-dihydro- [4,7] phenantrolines against single-stranded positive-sense RNA genome viruses Bioorg. Med. Chem. (2007) 15: 1914-1927   Chang KA et al., The role of S100a9 in the pathogenesis of Alzheimer's disease: the therapeutic effects of S100a9 knockdown or knockout. Neurodegener Dis 2012, 10 (1-4): 27-9   Chaudhari K et al., Novel and Facile Transformation of N, N-Disubstituted Glycylamides into Corresponding Cyanamides by Using Pentavalent Iodine Reagents in Combination with Tetraethylammonium Bromide. Synlett 2007, 18, 2815-2818   Cheng P et al., Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med 2008, 205 (10), 2235-49   Deane R et al., A multimodal RAGE-specific inhibitor reduces amyloid b-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest 2013. 122 (4): 1377-92   Foell D et al., S100 proteins in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol 2007, 81: 28-37   Foell D et al., Proinflammatory S100 proteins in arthritis and autoimmune disease. Arthritis Rheum 2004, 50, 3762-3771   Ghavami S et al., S100A8 / S100A9 at low concentration promoter tumor cell growth via RAGE ligation and MAP kinase-dependent pathway. J Leukoc Biol 2008, 83 (6), 1484-92   Ha T et al., S100a9 knockdown decreases the memory impairment and the neuropathology in Tg2576 mice, AD animal model. PLoS one 2010, 5 (1): e8840   Hibino T et al., S100A9 is a novel ligand of EMMPRIN that promotes melanoma metastasis. Cancer Res 2012 Nov 7 Epub ahead of print   Hiratsuka S et al., Tumor-mediated upregulation of chemoattractants and recruitment of myeloid cells. Nat Cell Biol. 8 (12), 1369-75 (2006)   Marenholz I et al., S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature). BBRC 2004, 322: 1111-22   Ryckman C et al., Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8 / A9 induce neutrophil chemotaxis and adhesion J. Immunol. 170, 3233-42 (2003)   Shepherd CE et al., Inflammatory S100A9 and S100A12 proteins in Alzheimers disease. Neurobiol Aging 2006, 27: 1554-1563   Sinha P et al., Proinflammatory S100 proteins regulate the ackumulation of myeloid-derived suppressor cells. J Immunol 2008, 181: 4666-4675   Srikrishna G et al., S100A8 and S100A9: New insights into their roles in malignancy. J Innate Immun 2012, 4: 31-40    Vogl T et al., Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, and endotoxin-induced shock. Nat Med 2007, 13 (9): 1042-9   Wang L et al., Increased myeloid-derived suppressor cells in gastric cancer correlate with cancer stage and plasma S100A8 / A9 proinflammatory proteins. J Immunol 2013, 190: 794-804   You L et al., Silica gel accelerated aza-Michael addition of amines to α, β-unsaturated amides. Tetrahedron Lett. 2008, 49, 5147-5149

In a first aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:

In the above formula (I)

R _A, R _B and R _C are independently H, halogen, cyano, R ₁ O, R ₁ O optionally substituted C1-C6 optionally substituted alkyl, R ₁ O C3-C6-cycloalkyl, R _{2 C (O), R 3} S, R 4 S (O) 2, R 5 OC (O), (R 6 ON) C (R 7), R 8 R 9 NC (O), R 10 R 11 N _{a, R 12 S (O) 2} NR 13, R 14 S (O) 2 NR 15 C (O), optionally substituted with one or more moieties R ₁₆ phenyl, and at least one moiety R ₁₆ an optionally substituted C 5- or 6-membered heterocyclyl, or

One of R _A and R _C together with R _B forms a bi-radical - (CH ₂ ) _m -, where m is an integer from 3 to 5 and the other of R _A and R _C is H, halogen, no, R ₁ O, R ₁ O optionally substituted C1-C6 alkyl, R ₁ O in an optionally substituted _{C3-C6-cycloalkyl, R 2 C (O),} R 3 S, R 4 S (O) _{2, R 5 OC (O)} , (R 6 ON) C (R 7), R 8 R 9 NC (O), R 10 R 11 N, R 12 S (O) 2 NR 13, R 14 S (O _{) 2 NR 15 C (O)} , optionally substituted with optionally substituted with one or more R ₁₆ moiety is phenyl, and at least one moiety R ₁₆ 5- or 6-immunogenicity is selected from heterocyclyl;

Each R ₁₆ is independently halogen, cyano, nitro, R ₁₇ O, R ₁₇ O in an optionally substituted C1-C6 alkyl, R ₁₇ O in an optionally substituted C3-C6-cycloalkyl, R ₁₈ C (O _{), R 19 S, R 20} S (O) 2, R 21 OC (O), (R 22 ON) C (R 23), R 24 R 25 NC (O), R 26 R 27 N, R 28 S (O) ₂ NR ₂₉ and R ₃₀ S (O) ₂ NR ₃₁ C (O);

R ₁ -R ₃₁ are each independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl;

W is a double bond or X ₁ -X ₂ -X ₃ ;

X ₁ is C 1 -C 2 alkylene optionally substituted by R ₃₂ O or C 1 -C 4 alkyl;

X ₂ is O or is omitted;

X ₃ is a direct bond or a C 1 -C 2 alkylene optionally substituted with R ₃₂ O or C 1 -C 4 alkyl;

R ₃₂ is selected from H and C 1 -C 4 alkyl;

R _D is C1-C6 alkyl or a cyclic moiety selected from phenyl, 4- to 6-membered heterocyclyl, C4-C6 cycloalkyl or C5-C6 cycloalkenyl, wherein said cyclic moiety is Is optionally substituted with one or more R < _{33 &} gt ;;

Each R ₃₃ is independently selected from the group consisting of halogen, cyano, C 1 -C 6 alkyl optionally substituted with R ₃₄ O, C 3 -C 6 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl, R ₃₄ O, R ₃₅ OC (O), R ₃₆ S (O) ₂ , R ₃₇ C (O), R ₃₈ R ₃₉ N, R ₄₀ R ₄₁ N (CO); Two R ₃₃ bonded to one and the same carbon atom together with the carbon atoms to which they are attached form a 4- to 6-membered ring optionally containing one or more heteroatoms in the ring;

R ₃₄ is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with R ₄₂ O;

Each of R ₃₅ -R ₃₆ is independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl;

R ₃₇ is independently selected from C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted with R ₄₃ O;

R ₃₈ and R ₃₉ are independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted with R ₄₄ R ₄₅ N or R ₄₆ O, or

R ₃₈ and R ₃₉ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring optionally containing one or more other heteroatoms and optionally substituted with C 1 -C 6 alkyl;

R ₄₀ and R ₄₁ are independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted with R ₄₇ R ₄₈ N or R ₄₉ O, or

R ₄₀ and R ₄₁ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring optionally containing one or more different heteroatoms and optionally substituted by C 1 -C 6 alkyl;

R ₄₄ and R ₄₅ are independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, or

R ₄₄ and R ₄₅ together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring optionally containing one or more other heteroatoms and optionally substituted by C 1 -C 6 alkyl;

R ₄₇ and R ₄₈ are independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, or

R ₄₇ and R ₄₈ together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring optionally containing one or more other heteroatoms and optionally substituted by C 1 -C 6 alkyl;

R ₄₂ , R ₄₃ , R ₄₆ and R ₄₉ are independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl;

Any alkyl is optionally substituted with one or more F.

The compounds of formula (I) as defined herein are usable as inhibitors of the interaction between S100A9 and its interaction partners, such as RAGE, TLR4 and EMMPRIN. Thus, in another aspect, compounds of formula (I) as defined herein above are useful for use as an interaction inhibitor between S100A9 and its interaction partner, and for use in the treatment of disorders associated with the function of S100A9, such as inflammatory diseases, neurodegenerative diseases, For the treatment of autoimmune diseases and cancers.

In one aspect, the compounds of formula (I) are provided for use in therapy, for example, for the treatment of inflammatory diseases, neurodegenerative diseases, autoimmune diseases and cancer.

In another aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The pharmaceutical composition of the present invention can be used for the treatment of diseases selected from inflammatory diseases, autoimmune diseases, neurodegenerative diseases and cancer.

Figure 1 is a schematic illustration of an assay inhibiting the interaction between biotinylated human S100A9 and human RAGE-Fc using a small molecule S100A9 binder.
2 is a graph showing the competitive binding of the compound of Example 13 (ABR 238219) to S100A9 in the presence of ( A ) RAGE and ( B ) TLR4. In the analysis, S100A9 was injected with ~ 1.3 μg / mL for amine-coupled human RAGE / Fc (density ~ 4.2 kRU) or TLR4 (density ~ 2900 resonance units) + 0.391-200 μM ABR-238219 (2 min; 30 [mu] l / min). (A) RAGE or (B) the response (Y axis) representing the% binding of S100A9 to TLR4 was plotted against the competition factors and applied to a sigmoid-type dose-response model. Assay Buffer - Containing 10 mM HEPES, 0.15 M NaCl, pH 7.4 (HBS buffer) + 0.005% v / v surfactant P20, 1 mM Ca ²⁺ and 20 μM Zn ²⁺ . After each cycle, the cells were regenerated by 30 펄스 pulse of 3 mM EDTA solution in HBS buffer.
Figure 3 is a graph showing (A) tumor growth according to continuous caliper measurements. The mice were inoculated with sc with tumor cells and treatment with Example 118 (a) (ABR 239071) was started the following day. The therapeutic (30 mg / kg) was given orally daily. (A) measuring tumor growth by continuous caliper measurements; (B) Last day (16 days), a bar chart showing the weight of the tumor. Tumor growth and weight differences between treatment groups were statistically evaluated by non-parametric only-Whitney U test, p <0.05. The error bar displays SEM.

Some definitions of terms used herein are provided below. It should be noted that this list is not exhaustive, and any terms and expressions used herein should be understood as ordinary meanings unless otherwise stated or clear from the context. Thus, for example, the term alkyl, either alone or as part of a radical, includes straight chain or branched chain alkyl of the general formula C _n H _{2n + 1} .

을 지칭한다.The term alkenyl refers to the bi radical of formula - (C _n H _2n ) -. For example, C2 alkenyl formula -CH ₂ CH ₂ - the radicals, that is,

Quot;

The term C1-C6 alkyl is any alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.

The term C1-C4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

The term C1-C3 alkyl includes methyl, ethyl, n-propyl and isopropyl.

The term cycloalkyl refers to a cyclic alkyl radical of the general formula C _n H _2n-1 .

The term cycloalkenyl refers to a cyclic alkenyl radical of the general formula C _n H _2n-3 .

The term C3-C6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

의 C₆H₅ 라디칼을 지칭한다.The term &quot; phenyl &

&Lt; / RTI &gt; of the C ₆ H ₅ radical.

The term heterocyclyl refers to a saturated or unsaturated, aromatic or non-aromatic cyclic moiety comprising at least one heteroatom in the ring.

The term heteroaryl refers to an aromatic heterocyclyl, such as pyridyl (also referred to as pyridinyl), tetrazolyl, furyl, or pyrimidinyl.

의 C₅NH₅ 라디칼을 지칭한다.The term pyridyl includes pyrimidines such as 2-pyridyl, 3-pyridyl and 4-

It refers to a C _{5 5} NH radical.

의 C₄N₂H₄ 라디칼을 지칭한다.The term pyrimidinyl includes 2-pyrimidinyl, 4-pyrimidinyl and 5-pyrimidinyl,

Quot; C ₄ N ₂ H ₄ &quot; radical.

The term thiazolyl refers to 1,2-thiazolyl and 1,3-thiazolyl.

의 라디칼을 지칭한다.The term 1,2-thiazolyl means a group represented by the formula of 1,2-thiazol-3-yl, 1,2-thiazolyl-4-yl and 1,2-

&Lt; / RTI &gt;

의 라디칼을 지칭한다.The term 1,3-thiazolyl means a group represented by the formula of 1,3-thiazol-2-yl, 1,3-thiazol-4-yl,

&Lt; / RTI &gt;

The term halogen refers to F, Cl, Br and I, preferably F, Cl and Br.

The term hydroxy refers to a radical of formula-OH.

The term alkoxy refers to a radical of formula RO wherein R is alkyl.

의 라디칼을 지칭한다.The term RO,

&Lt; / RTI &gt;

The term cyano refers to radicals of the formula -C? N (i.e. -CN).

의 모이어티를 지칭한다.The term RC (O)

Lt; / RTI &gt;

의 라디칼이다.The radical RS is represented by the formula

Lt; / RTI &gt;

의 라디칼을 지칭한다.The term RS (O) ₂ is formula

&Lt; / RTI &gt;

의 라디칼을 지칭한다.The term ROC (O)

&Lt; / RTI &gt;

의 라디칼을 지칭한다.The term (RON) C (R '

&Lt; / RTI &gt;

의 라디칼을 지칭한다.The term &lt; RTI ID =

&Lt; / RTI &gt;

의 라디칼을 지칭한다.The term RR'NC (O)

&Lt; / RTI &gt;

의 라디칼을 지칭한다.The term RS (O) ₂ NR '

&Lt; / RTI &gt;

의 라디칼을 지칭한다.The term RS (O) ₂ NR'C (O)

&Lt; / RTI &gt;

"Optional" or "optionally" means that the subsequently described phenomenon or circumstance may, but need not necessarily occur, encompass the case where the phenomenon or circumstance occurs and the case where it does not.

"Pharmaceutically acceptable" means useful in the manufacture of pharmaceutical compositions that are generally safe, non-toxic, and not biologically unacceptable, including those suitable for veterinary as well as pharmaceutical use do.

The term pharmaceutically acceptable salts of the compounds refers to those salts which are pharmaceutically acceptable as defined herein and which possess the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; Or organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxynaphthoic, , Acid addition salts formed with lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, miconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid and trimethylacetic acid; Or the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion; Or salts formed when coordinated with organic or inorganic bases. Acceptable organic bases include, for example, diethanolamine, ethanolamine, N-methylglucamine, triethanolamine and tromethamine. Acceptable inorganic bases include, for example, aluminum hydroxides, calcium hydroxides, potassium hydroxides, sodium carbonate, and sodium hydroxide.

When a chiral carbon is present in a chemical structure, unless otherwise stated, all stereoisomers related to the chiral carbon are intended to be included in the structure. Using the Cahn-Ingold-Prelog RS labeling scheme, any asymmetric carbon atom may be present in the (R) - or (S) - configuration and the compound may be a mixture of its stereoisomers, for example as a racemic mixture or Only one stereoisomer can exist.

Some of the compounds of the present invention may exist in tautomeric forms. Any such tautomer is contemplated as falling within the scope of the present invention.

In addition, in the compounds of formula (I) as defined herein, any hydrogen atom may be substituted with deuterium ( ² H), and any such deuterated Compounds of formula (I) are considered to be within the scope of the present invention.

"Therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect treatment of the disease state. "Therapeutically effective amount" will vary depending on the compound, the disease state being treated, the severity of the therapeutic disease, the age and relative health status of the individual, the route and form of administration, and the medical judgment of the primary or veterinary practitioner.

As used herein, the term " treating "or" treating "is an approach to achieve beneficial or desired outcomes, such as clinical performance. Beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in the severity of the disease, stabilized (i.e., not worsening) condition of the disease, prevention of the spread of the disease, Or amelioration or amelioration of a disease state, and (partial or complete) remission, whether detectable or undetectable. In addition, the term may refer to an extension of survival as compared to the expected survival rate in non-treatment.

The term mammal refers to a human or any mammalian animal, for example, a primate, farm animal, pet or laboratory animal. Examples of such animals include monkeys, cows, sheep, horses, pigs, dogs, cats, rabbits, mice, and rats. Preferably, the mammal is a human.

The term cancer refers to any malignant proliferation or tumor caused by abnormal and uncontrolled cell division; It can spread to other parts of the body through the lymphatic system or blood system and includes both solid tumors and blood-borne tumors. Examples of cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, anorectal cancer, A childhood cerebral astrocytoma, a childhood cerebral astrocytoma, a basal cell carcinoma, a biliary cancer, an extrahepatic bile duct cancer, Intrahepatic bile duct cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain tumor, brain stem, The brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, visual pathway and pituitary gland It has been suggested that the pathophysiology of glioma may be related to the pathology and hypothalamic glioma, breast cancer, bronchial adenomas / carcinoids, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorder, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasm, mycosis fungoides, chronic myeloproliferative disorder, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, It has been reported that the incidence of extragonadal adenocarcinoma is higher than that of extragonadal germ cell tumors. gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal tumor, gastrointestinal stromal tumor, gastrointestinal stromal tumor, ), Germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor, glioma, head and neck cancer, hepatocellular (liver, Hepatocellular carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, ocular cancer, Kaposi's sarcoma, renal cancer, laryngeal cancer, Acute lymphoblastic leukemia, acute myeloid leukemia, hairy cell leukemia, lip and oral cavity cancer, lung cancer, non-small cell &lt; RTI ID = 0.0 & Non-small lung cancer cell lung cancer, small cell lung cancer, non-Hodgkin's lymphoma, primary central nervous system lymphoma, Waldenstrom's macroglobulinemia Merkel cell carcinoma, malignant mesothelioma, metastatic squamous neck cancer, cancer of the tongue, melanoma, and the like), melanoma (malignant melanoma), intraocular (melanoma) Multiple endocrine neoplasia syndrome, myelodysplastic syndromes, myelodysplastic / myeloproliferative diseases, nasopharyngeal cancer, neuroblastoma, adenocarcinoma, cancer, ovarian cancer, oral cavity cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian cancer, ovarian cancer, low malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, brown Pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleural effusion, (Ewing's sarcoma family of tumors), soft tissue sarcoma, soft tissue sarcoma, cervical cancer (e. G., Sarcoma) uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), small intestine cancer, squamous cell carcinoma, testicular cancer a testicular cancer, a throat cancer, a thymoma, a thymic carcinoma and a thymic carcinoma, a thyroid cancer, a pyelonephritis, and other ureteral or transitional cell carcinoma of the renal pelvis and ureter and other urinary organ, gestational trophoblastic tumor, urethral cancer, vaginal cancer, vulvar cancer, and Wilm's tumor.

The term autoimmune disorder (or autoimmune disease) refers to any disorder that causes an inappropriate immune response to a substance and tissue normally present in the body (autoimmune). Such reactions may be confined to specific organs, or may involve specific tissues at various sites. Examples of autoimmune disorders include acute disseminated encephalomyelitis (ADEM), Addison's disease, agammaglobulinemia, alopecia areata, amyotrophic lateral sclerosis, Ankylosing spondylitis, antiphospholipid syndrome, antisynthetase syndrome, atopic allergy, atopic dermatitis, autoimmune aplastic anemia, autoimmune aplastic anemia, Autoimmune cardiomyopathy, autoimmune enteropathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoma, Autoimmune lymphoproliferative syndrome, autoimmune peripheral neuropathy autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune urticarial, autoimmune uveitis, Balo concentric sclerosis, Behcet's disease, Berger's disease, Bickerstaff's encephalitis, Blau's disease, Syndrome, bullous pemphigoid, Castleman's disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic recurrent disease, Chronic recurrent multifocal osteomyelitis, chronic obstructive pulmonary disease Chronic obstructive pulmonary disease, Churg-Strauss syndrome, cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, complement two- component 2 deficiency, contact dermatitis, cranial arteritis, CREST syndrome, Crohn's disease (one of two types of idiopathic inflammatory bowel disease "IBD"), Cushing's Syndrome, Dermatitis herpetiformis, dermatomyositis, type 1 diabetes mellitus type 1, diffuse cutaneous leukocytoclastic angiitis, Dego's disease, Dercum's disease, dermatitis herpetiformis, dermatomyositis, Diffuse cutaneous systemic sclerosis, Dressler's syndrome, drug-induced lupus, discoid lupus erythema (lupus erythematosus) tosus, eczema, endometriosis, enthesitis-related arthritis, eosinophilic fasciitis, eosinophilic gastroenteritis, epidermolysis bullosa, epidermolysis bullosa acute myelogenous leukemia, acquisita, erythema nodosum, erythroblastosis fetalis, essential mixed cryoglobulinemia, Evan's syndrome, fibrodysplasia ossificans progressive, fibrous dysplasia, (Idiopathic pulmonary fibrosis), gastritis, gastrointestinal pemphigoid, glomerulonephritis, Goodpasture ' s syndrome, Graves ' 'disease, Guillain-Barre syndrome (GBS), Hashimoto's encephalo pathogens, Hashimoto's thyroiditis, Henoch-Schonlein purpura, herpes gestationis (aka pregnancy rituximab), Hidradenitis suppurativa, Hughes-Stokes syndrome Hypogammaglobulinemia, idiopathic inflammatory demyelinating diseases, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, IgA nephropathy &lt; RTI ID = 0.0 &gt; IgA nephropathy, inclusion body myositis, chronic inflammatory demyelinating polyneuropathy, interstitial cystitis, juvenile idiopathic arthritis (aka pediatric rheumatoid arthritis) Kawasaki's disease, Lambert-Eaton myasthenic s leukocytoclastic vasculitis, lichen planus, lichen sclerosus, linear IgA disease, lupoid hepatitis (aka autoimmune hepatitis), leukopenia, Lupus erythematosus, Majeed syndrome, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, morphea, Mucha-Haberman disease The present invention relates to a method of treating multiple sclerosis, including multiple sclerosis, myasthenia gravis, myositis, narcolepsy, optic nerve palsy (including acute myeloid leukemia), multiple sclerosis (multiple sclerosis, multiple sclerosis, neuromyelitis optica (also referred to as Devic's disease), neuromyotonia, occular cicatricial pemphigoid, ocular temporal convulsions, Pediatric autoimmune neuropsychiatric disorders associated with streptococcus), edematous cerebellar degeneration (paraneoplastic syndrome), pediatric autoimmune neuropsychiatric disorders associated with streptococcal disease, cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry Romberg syndrome, Parsonage-Turner syndrome, pars planitis, pemphigus pemphigus, pemphigus vulgaris, pernicious anemia, perivenous encephalomyelitis, POEMS syndrome, polyarteritis nodosa, rheumatic polymyalgia rheumatic, polymyositis, primary biliary cirrhosis primary biliary cirrhosis, primary sclerosing cholangitis, progression Psoriasis, psoriatic arthritis, pyoderma gangrenosum, pure red cell aplasia, Rasmussen's encephalitis, Raynaud's phenomenon, A variety of diseases such as Raynaud's phenomenon, relapsing polychondritis, Reiter's syndrome, restless leg syndrome, retroperitoneal fibrosis, rheumatoid arthritis, rheumatic fever, Other forms of APS include schizophrenia, schizophrenia, other forms of APS, Schnitzler syndrome, scleritis, scleroderma, serum sickness, fever, sarcoidosis, schizophrenia, ), Sjogren's syndrome, spondyloarthropathy, stiff person syndrome, subacute &lt; RTI ID = 0.0 &gt; A bacterial endocarditis, subacute bacterial endocarditis (SBE), Susac's syndrome, Sweet's syndrome, sympathetic ophthalmia, systemic lupus erythematosis, Takayasu's arteritis, It is well known that it can be used for the treatment of temporal arteritis (also referred to as "giant cell arteritis"), thrombocytopenia, Tolosa-Hunt syndrome, transverse myelitis, , ulcerative colitis (one of two types of idiopathic inflammatory bowel disease "IBD"), undifferentiated connective tissue disease different from mixed connective tissue disease, undifferentiated spondyloarthropathy, urticarial vasculitis, vasculitis, vitiligo, and Wegener's granuloma It has (Wegener's granulomatosis).

The term inflammatory disorder (or inflammatory disease) refers to a pathological condition associated with inflammation, typically caused by leukocyte infiltration. Inflammatory disorders may be acute or chronic. Examples of inflammatory disorders include, but are not limited to, inflammatory skin diseases, psoriasis and atopic dermatitis, systemic sclerosis and sclerosis, inflammatory bowel disease (IBD) -related reactions (e.g. Crohn's disease and ulcerative colitis), ischemic reperfusion injury, Myocardial infarction, cardiac arrest, post-cardiac reperfusion and percutaneous transluminal coronary angioplasty stenosis, stroke, and abdominal aortic aneurysm, cerebral edema due to stroke, head trauma, low blood volume Shock, suffocation, adult respiratory distress syndrome, acute-lung injury, Behcet's disease, dermatomyositis; Polymyositis; Multiple sclerosis (MS); dermatitis; meningitis; encephalitis; Secondary multiple organ damage syndrome due to uveitis, osteoarthritis, lupus nephritis, autoimmune diseases such as rheumatoid arthritis (RA), Sjogren's syndrome, vasculitis, leukocyte leaking disease, central nervous system (CNS) inflammatory disorder, sepsis or trauma An inflammatory disease of the lungs such as pleurisy, alveolitis, vasculitis, pneumonia, acute respiratory distress syndrome, chronic obstructive pulmonary disease, chronic obstructive pulmonary disease, alcoholic hepatitis, bacterial pneumonia, antigen-antibody complex mediated diseases such as glomerulonephritis, sepsis, , Chronic bronchitis, bronchiectasis, diffuse pan bronchitis, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), and cystic fibrosis.

The term neurodegenerative disorder (or neurodegenerative disease) refers to a disorder associated with a gradual loss of neuronal structure or function that affects the structure or function of the brain, vertebral or peripheral nervous system. Examples of neurodegenerative disorders include, but are not limited to, mitochondrial brain laxity and ataxia syndrome, ataxia syndrome such as Friedreich's ataxia and spinal cord cerebral ataxia (SCA), spinal cord injury, familial and sporadic amyotrophic lateral sclerosis Familial and sporadic Alzheimer &apos; s disease, Huntington &apos; s disease, olfactory limb cerebellar atrophy, multiple system atrophy, progressive supranuclear palsy, diffuse rheumatic diseases and synucleinopathies, Down syndrome, corticodentatonigral degeneration, progressive familial interstitial epilepsy, strionigral degeneration, torsion dystonia, familial tremor, Jill de la Tourette's syndrome Gilles de la Tourette syndrome and Hallervorden-Spatz disease.

The term excipient refers to a pharmaceutically acceptable chemical agent, such as a chemical agent, known to those skilled in the art of pharmacy to assist in the administration of the agent. It is a compound which is generally safe, non-toxic, not biologically and otherwise unsuitable for use in the preparation of pharmaceutical compositions, and includes excipients which are acceptable for veterinary use as well as human pharmaceutical use. Examples of excipients include binders, surfactants, diluents, disintegrants, lubricants and lubricants.

In a first aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.

In the compounds of formula (I), moiety R _A, R _B and R _C are independently optionally with H, halogen, cyano, R ₁ O, R ₁ O a C1-C6 alkyl, R ₁ O, optionally substituted with substituted _{C3-C6-cycloalkyl, R 2 C (O),} R 3 S, R 4 S (O) 2, R 5 OC (O), (R 6 ON) C (R 7), R 8 R 9 (O), R ₁₀ R ₁₁ N, R ₁₂ S (O) ₂ NR ₁₃ , R ₁₄ S (O) ₂ NR ₁₅ C (O), phenyl optionally substituted with one or more R ₁₆ moieties, and one Or 5-or 6-membered heterocyclyl optionally substituted with at least one R ₁₆ moiety; or

One of R _A and R _C together with R _B forms a bi-radical - (CH ₂ ) _m - wherein m is an integer from 3 to 5 and the other of R _A and R _C is H, halogen, cyano, R ₁ O, R ₁ O optionally substituted C1-C6 alkyl, optionally substituted C3-C6-cycloalkyl in _{R 1 O, R 2 C (} O), R 3 S, R 4 S (O) 2, R 5 _{OC (O), (R 6} ON) C (R 7), R 8 R 9 NC (O), R 10 R 11 N, R 12 S (O) 2 NR 13, R 14 S (O) 2 NR 15 C (O), is selected from one or more of R ₁₆ is optionally substituted with a phenyl moiety, and one or more R ₁₆ moiety in an optionally substituted 5-or 6-immunogenic heterocyclyl.

In some embodiments, R _A , R _B and R _C are independently selected from H, halogen, cyano, _{C 1} -C 6 alkyl optionally substituted with R ₁ O, R ₁ O, C 3 -C 6 alkyl optionally substituted with R ₁ O -C6 _{cycloalkyl, R 2 C (O),} R 3 S, R 4 S (O) 2, R 5 OC (O), (R 6 ON) C (R 7), R 8 R 9 NC (O) _{, R 10 R 11 N, R} 12 S (O) 2 NR 13, R 14 S (O) 2 NR 15 C (O), optionally substituted with one or more R ₁₆ moiety is phenyl, and one or more R ₁₆ moiety 5-or 6-membered heterocyclyl which is optionally substituted by &lt; RTI ID = 0.0 &gt;

In some other embodiments, one of R _A and R _C together with R _B forms a bi-radical - (CH ₂ ) _m -, wherein m is an integer from 3 to 5, and the other of R _A and R _C is H, halogen, cyano, R ₁ O, R ₁ O optionally substituted C1-C6 alkyl, optionally substituted C3-C6-cycloalkyl, R ₂ C (O) substituted with R ₁ O substituted with, in R ₃ S, R ₄ S _{(O) 2, R 5 OC} (O), (R 6 ON) C (R 7), R 8 R 9 NC (O), R 10 R 11 N, R 12 S (O) 2 NR 13, R 14 _{S (O) 2 NR 15 C} (O), is selected from one or more of R ₁₆ is optionally substituted with a phenyl moiety, and one or more R ₁₆ moiety in an optionally substituted 5-or 6-immunogenic heterocyclyl.

Thus, the moiety R _A is H, halogen, cyano, R ₁ O, R ₁ O optionally substituted C1-C6 alkyl, R ₁ O in an optionally substituted C3-C6-cycloalkyl, R ₂ C (O _{), R 3 S, R 4} S (O) 2, R 5 OC (O), (R 6 ON) C (R 7), R 8 R 9 NC (O), R 10 R 11 N, R 12 S _{(O) 2 NR 13, R} 14 S (O) 2 NR 15 C (O), at least one R ₁₆ is optionally substituted with a phenyl moiety, and a 5-or 6, optionally substituted with one or more R ₁₆ moiety, - &lt; / RTI &gt;heterocyclyl; Or together with R _B form a bi-radical - (CH ₂ ) _m - wherein m is an integer from 3 to 5.

In some embodiments, R _A is H, halogen, cyano, R ₁ O, R ₁ O optionally substituted C1-C6 alkyl, R ₁ O in an optionally substituted C3-C6-cycloalkyl, R ₂ C _{(O), R 3 S,} R 4 S (O) 2, R 5 OC (O), (R 6 ON) C (R 7), R 8 R 9 NC (O), R 10 R 11 N, R _{12 S (O) 2 NR 13} , R 14 S (O) 2 NR 15 C (O), at least one R ₁₆ is optionally substituted with a phenyl moiety, and optionally substituted 5 with one or more R ₁₆ moiety, Or 6-membered heterocyclyl.

In some embodiments, R _A is H, halogen, cyano, R ₁ O, R ₁ O optionally substituted C1-C6 alkyl, R ₁ O in an optionally substituted C3-C6-cycloalkyl, R ₂ C _{(O), R 3 S,} R 4 S (O) 2, R 5 OC (O), (R 6 ON) C (R 7), R 8 R 9 NC (O), R 10 R 11 N, R ₁₂ S (O) ₂ NR ₁₃ , and R ₁₄ S (O) ₂ NR ₁₅ C (O).

In some embodiments, R _A is H, halogen, cyano, R ₁ O optionally substituted C1-C6 alkyl, optionally substituted C3-C6-cycloalkyl in _{R 1 O, R 2 C (} O), R ₃ S, R ₄ S (O) ₂ , R ₅ OC (O), R ₁₂ S (O) ₂ NR ₁₃ , and R ₁₄ S (O) ₂ NR ₁₅ C (O).

In some embodiments, R _A is selected from H, halogen, C 1 -C 6 alkyl and R ₂ C (O) such as H, halogen and C 1 -C 6 alkyl, or is selected from H and halogen.

In some embodiments, R _A is H.

In some other embodiments, R _A is selected from halogen, C 1 -C 6 alkyl and R ₂ C (O) such as C 1 -C 6 alkyl and R ₂ C (O), for example R _A is R ₂ C O) or R &lt; _{A &gt;} is C1-C6 alkyl.

In some embodiments, R _A is H, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, R ₂ C (O), R ₄ S (O) ₂ , R ₅ OC _{12 S (O) 2 NR 13} , R 14 S (O) 2 NR 15 C (O), at least one R ₁₆ is optionally substituted with a phenyl moiety, and optionally substituted 5 with one or more R ₁₆ moiety, Or 6-membered heterocyclyl; For example, H, a halogen, is selected from one or more of R ₁₆ is optionally substituted with one or more R ₁₆ moiety is phenyl and optionally substituted by a 5-or 6-immunogenic moiety heterocyclyl, for example H, at least one R ₁₆ is optionally substituted with a phenyl moiety and one or more R ₁₆ as a moiety selected from optionally substituted 5-or 6-immunogenic or heterocyclyl, or one or more R ₁₆ optionally substituted by phenyl moiety And 5- or 6-membered heterocyclyl optionally substituted with one or more R ₁₆ moieties.

If In some embodiments, R _A is at least one R ₁₆ is a moiety, optionally substituted phenyl or optionally substituted with one or more R ₁₆ moiety is a 5-or 6-immunogenic heterocyclyl, more specifically a Gt; R &lt; ₁₆ &gt; moieties. If In some embodiments, R _A is at least one R ₁₆ is a moiety, optionally substituted phenyl or optionally substituted with one or more R ₁₆ moiety is a 5-or 6-immunogenic heterocyclyl, more specifically a Lt; / RTI &gt; is a 5- or 6-membered heterocyclyl optionally substituted with at least one R &lt; ₁₆ &gt; moiety.

Moiety R _B is H, halogen, cyano, R ₁ O, R ₁ O optionally substituted C1-C6 alkyl, optionally substituted C3-C6-cycloalkyl in _{R 1 O, R 2 C (} O), R ₃ S, R ₄ S (O) ₂ , R ₅ OC (O), R ₆ ONC (R ₇ ), R ₈ R ₉ NC (O), R ₁₀ R ₁₁ N, R ₁₂ S _{) 2 NR 13, R 14 S} (O) 2 NR 15 C (O), one or more R ₁₆ moiety in an optionally substituted phenyl, and one or more of R ₁₆ an optionally substituted 5-or 6-heteroaryl as immunogenic moiety Cyclic &lt; / RTI &gt; Or by a radical of an integer m of 3 to 5 with the R _A or R _C - to form a - (CH _{2) m.}

In some embodiments, R _B is H, halogen, cyano, R ₁ O, R ₁ O optionally substituted C1-C6 alkyl, R ₁ O in an optionally substituted C3-C6-cycloalkyl, R ₂ C _{(O), R 3 S,} R 4 S (O) 2, R 5 OC (O), (R 6 ON) C (R 7), R 8 R 9 NC (O), R 10 R 11 N, R _{12 S (O) 2 NR 13} , R 14 S (O) 2 NR 15 C (O), optionally substituted with one or more R ₁₆ is optionally substituted with a phenyl moiety and one or more R ₁₆ moiety is a 5-or 6-membered heterocyclyl.

In some embodiments, R _B is H, halogen, R ₁ O, R ₁ O optionally substituted C1-C6 alkyl, R ₁ O, optionally substituted with C3-C6 cycloalkyl, one or more R ₁₆ moiety And 5- or 6-membered heterocyclyl optionally substituted by one or more R &lt; ₁₆ &gt; moieties.

In some embodiments, R _B is an optionally substituted 5-or 6-immunogenic heterocyclyl optionally substituted with phenyl or one or more R ₁₆ moiety with one or more R ₁₆ moiety.

In some embodiments, R _B is H, halogen, R ₁ O, with R ₁ O from optionally optionally substituted by a substituted C1-C6 alkyl and R ₁ O C3-C6-cycloalkyl, for example, H, Halogen and C1-C6 alkyl optionally substituted with R &lt; ₁ &gt; O.

In some embodiments, R _B is selected from H, halogen, R ₁ O, optionally substituted C1-C6 alkyl and optionally substituted C3-C6-cycloalkyl in R ₁ O with, for example, from H and halogen .

In some embodiments, R _B is selected from H, halogen, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, for example from H, halogen and C 1 -C 6 alkyl, eg, from H and C 1 -C 6 alkyl .

In some embodiments, R _B is optionally from a halogen, R ₁ O, optionally substituted C1-C6 alkyl and optionally substituted C3-C6-cycloalkyl in R ₁ O with, for example, a halogen, and R ₁ O Substituted C1-C6 alkyl; Or halogen and is selected from C1-C6 alkyl, such as R _B is a halogen.

In some embodiments, R _B is H.

Moiety R _C is H, halogen, cyano, R ₁ O, R ₁ O optionally substituted C1-C6 alkyl, R ₁ O in an optionally substituted C3-C6-cycloalkyl, R ₂ C (O), R ₃ S, R ₄ S (O) ₂ , R ₅ OC (O), R ₆ ONC (R ₇ ), R ₈ R ₉ NC (O), R ₁₀ R ₁₁ N, R ₁₂ S _{) 2 NR 13, R 14 S} (O) 2 NR 15 C (O), one or more R ₁₆ moiety in an optionally substituted phenyl, and one or more of R ₁₆ an optionally substituted 5-or 6-heteroaryl as immunogenic moiety Cyclic or forms a bivalent radical - (CH ₂ ) _m - with R _B , where m is an integer from 3 to 5.

In some embodiments, R _C is H, halogen, cyano, R ₁ O, R ₁ O optionally substituted C1-C6 alkyl, R ₁ O in an optionally substituted C3-C6-cycloalkyl, R ₂ C _{(O), R 3 S,} R 4 S (O) 2, R 5 OC (O), (R 6 ON) C (R 7), R 8 R 9 NC (O), R 10 R 11 N, R _{12 S (O) 2 NR 13} , R 14 S (O) 2 NR 15 C (O), optionally substituted with one or more R ₁₆ is optionally substituted with a phenyl moiety and one or more R ₁₆ moiety is a 5-or 6-membered heterocyclyl.

In some embodiments, R _C is H, halogen, R ₁ O, R ₁ O optionally substituted C1-C6 alkyl, optionally substituted C3-C6-cycloalkyl in _{R 1 O, R 2 C (} O) , is selected from one or more of R ₁₆ is optionally substituted with one or more R ₁₆ moiety is phenyl and optionally substituted by a 5-or 6-immunogenic moiety heterocyclyl.

In some embodiments, R _C is an optionally substituted 5-or 6-immunogenic heterocyclyl or optionally substituted phenyl, or one or more R ₁₆ moiety with one or more R ₁₆ moiety.

In some embodiments, R _C is H, halogen, R ₁ O, R ₁ O optionally substituted optionally substituted C3-C6 cycloalkyl, and R ₂ C (O) substituted with C1-C6 alkyl, R ₁ O substituted with .

In some embodiments, R _C is H, halogen, R ₁ O, with R ₁ O from optionally optionally substituted by a substituted C1-C6 alkyl and R ₁ O C3-C6-cycloalkyl, for example, H, halogen, from optionally substituted C3-C6 cycloalkyl optionally a C1-C6 alkyl and R ₁ O-substituted by a R ₁ O, or H, halogen, C1-C6 alkyl and C3-C6 from cycloalkyl, in particular H, Halogen and C1-C6 alkyl, or H and C1-C6 alkyl.

In some embodiments, R _C is H.

In some embodiments, one of R _A and R _C together with R _B forms a bi-radical - (CH ₂ ) _m -, wherein m is an integer from 3 to 5, for example 3 or 4, or 3. In this embodiment, the other of R _A and R _C is H, halogen, cyano, R ₁ O, R ₁ O optionally substituted C1-C6 alkyl, optionally substituted with R ₁ O C3-C6 cycloalkyl _{alkyl, R 2 C (O),} R 3 S, R 4 S (O) 2, R 5 OC (O), (R 6 ON) C (R 7), R 8 R 9 NC (O), R 10 _{R 11 N, R 12 S (} O) optionally a _{2 NR 13, R 14 S (} O) 2 NR 15 C (O), one or more R _16, optionally substituted phenyl, and one or more R ₁₆ moiety is a moiety with Substituted 5- or 6-membered heterocyclyl. In these embodiments, the other of R _A and R _C is a preferably optionally substituted by H, halogen, cyano, R ₁ O, R ₁ O a C1-C6 alkyl, R ₁ O, optionally substituted with _{C3-C6-cycloalkyl, R 2 C (O),} R 3 S, R 4 S (O) 2, R 5 OC (O), (R 6 ON) C (R 7), R 8 R 9 NC (O from _{a), R 10 R 11 N,} R 12 S (O) 2 NR 13, and _{R 14 S (O) 2 NR} 15 C (O); For example, H, halogen, cyano, R ₁ O, R ₁ O optionally substituted C1-C6 _{alkyl, R 2 C (O),} R 3 S, R 4 S (O) 2, R 5 OC ( _{O), (R 6 ON)} C (R 7), R 8 R 9 NC (O), R 10 R 11 N, R 12 S (O) 2 NR 13, and _{R 14 S (O) 2 NR} 15 C (O); For example, from H, halogen and C1-C3 alkyl; For example, from H, F and methyl; Or H and F, in particular H.

In some embodiments, R _A, R _B, and R one or more of _C is an optionally substituted 5-or 6-heteroaryl immunogenic as optionally substituted phenyl, or one or more R ₁₆ moiety with one or more R ₁₆ moiety, Lt; / RTI &gt;

In some embodiments, R _A, R _B and R _C has one of the one or more R ₁₆ moiety in an optionally substituted optionally substituted phenyl, or one or more R ₁₆ moiety is a 5-or 6-immunogenic heterocycle It is a reel.

In some embodiments, R _A, R _B and R _C is one with one or more R ₁₆ moiety of the optionally substituted phenyl, or optionally substituted with one or more R ₁₆ moiety is a 5-or 6-immunogenic heterocycle When it is a reel, the remaining two of R _A , R _B and R _C are defined herein as defined above, but are optionally substituted with one or more R ₁₆ moieties, optionally substituted with one or more R ₁₆ moieties, Is not a substituted 5- or 6-membered heterocyclyl.

For example, in some embodiments, R _A, R _B and R _C is one or more than one of R ₁₆ an optionally substituted phenyl or optionally substituted with one or more R ₁₆ moiety is a 5- or 6-moiety The remaining two of R _A , R _B and R _C are independently selected from H, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and R ₂ C (O) Alkyl and R &lt; ₂ &gt; C (O), for example from H, F, Cl and C1-C3 alkyl; Or H, F and methyl; E., Both H or F, or both.

In some embodiments, R _A, R _B and R _C are independently H, halogen, cyano, C1-C4 _{alkyl, R 1 O, R 2 C} (O), R 3 S and R ₄ S (O) ₂ , or one of R _A and R _C together with R _B forms a bi-radical - (CH ₂ ) _m - wherein m is an integer from 3 to 5 and the other of R _A and R _C is H, halogen , cyano, are selected from C1-C4 _{alkyl, R 1 O, R 2 C} (O), R 3 S and R ₄ S (O) _2.

More preferably, when any of R _A , R _B and R _C is selected from halogen, it may be selected from F, Cl or Br, or from F and Cl, in particular Cl.

When any one of R _A , R _B and R _C is selected from _{C 1} -C 6 alkyl optionally substituted with R ₁ O and C 3 -C 6 cycloalkyl optionally substituted with R ₁ O, more specifically R ₁ O C ₁ -C 4 alkyl optionally substituted by R ₁ O, or C ₁ -C 3 alkyl optionally substituted by R ₁ O, in particular from R ₁ O Optionally substituted methyl.

In some embodiments, when any one of R _A , R _B, and R _C is selected from _{C 1} -C 6 alkyl optionally substituted with R ₁ O and C 3 -C 6 cycloalkyl optionally substituted with R ₁ O, Specifically from C1-C6 alkyl, or from C1-C4 alkyl, or from C1-C3 alkyl, especially methyl.

In some embodiments, when any of R _A , R _B, and R _C is selected from C 3 -C 6 cycloalkyl optionally substituted with R ₁ O, more particularly from C3-C6 cycloalkyl, or C3- C5 cycloalkyl, or C3-C4 cycloalkyl, for example cyclopropyl.

In some embodiments, R _A , R _B and R _C are all H, i.e. the compound of formula (I) is a compound of formula (Ia):

Wherein W and R _D are defined as defined herein.

In some other embodiments, at least one of R _A , R _B, and R _C is not H.

In some embodiments, R _A is defined herein as defined above but is not H; Or R _B is defined herein as defined above, but is not H.

In some embodiments, two of R _A , R _B, and R _C are not H, i.e., R _A and R _B are not H, or R _A and R _C are not H, or R _B And R _C is not H.

In some embodiments, R &lt; _A &gt; is H, wherein the compound may be represented by formula (Ib)

Wherein R _B , R _C , W and R _D are defined as defined herein, for example R _B and R _C are defined herein as defined above, but R _B and R _C are also H .

In some other embodiments, R _A is not H. In some embodiments, R _A and R _B are not H, and R _C is H. In some other embodiments, R _A and R _C are not H, and R _B is H.

In some embodiments, R _A is not H, and R _B and R _C are both H, in which case the compound can be represented by formula (Ic)

Wherein R _A , W and R _D are defined as defined herein.

When either R _A , R _B , and R _C is _{C 1} -C 6 alkyl optionally substituted with R ₁ O, R ₁ O or C 3 -C 6 cycloalkyl optionally substituted with R ₁ O, the moiety R ₁ Is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, for example from H, C1-C4 alkyl and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, the moiety R ₁ is selected from H and C ₁ -C 6 alkyl, for example from H and C 1 -C 4 alkyl, or from H and C 1 -C 3 alkyl, for example from H and CH ₃ , Especially H.

In some embodiments, the moiety R &lt; ₁ &gt; is defined herein as defined above but is not H; For example, R ₁ is CH ₃ .

In some embodiments, R _A, R _B and R _C of any of the R ₁ O, R ₁ O optionally substituted C1-C6 alkyl and R ₁ O in an optionally substituted C3-C6 selected from cycloalkyl, If, more specifically, R ₁ O and R ₁ O optionally substituted from C1-C6 alkyl, for example R ₁ O and R ₁ O in the optionally substituted C1-C3 alkyl, or R ₁ by O and R is selected from a C1-C2 alkyl optionally substituted by ₁ O, for the example, R ₁ O, R ₁ OCH ₂ and R ₁ may be selected from OCH (CH _3), in particular R ₁ O .

If any of R _A , R _B , and R _C is R ₂ C (O) then R ₂ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₂ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl, or from H, C 1 -C 3 alkyl and cyclopropyl. In some embodiments, R ₂ is selected from H and C 1 -C 6 alkyl, for example from H and C 1 -C 4 alkyl, or from H and C 1 -C 3 alkyl, for example, H, CH ₃ and (CH ₃ ) ₂ CH, in particular CH ₃ . In some embodiments, the moiety R &lt; ₂ &gt; is defined herein as defined above but is not H.

When any of R _A , R _B , and R _C is R ₃ S, then R ₃ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₃ is selected from H, C 1 -C 4 alkyl, and C 3 -C 4 cycloalkyl, or from H, C 1 -C 3, and alkylcyclopropyl. In some embodiments, R ₃ is selected from H and C 1 -C 6 alkyl, for example from H and C 1 -C 4 alkyl, or from H and C 1 -C 3 alkyl, for example from H and CH ₃ , especially CH ₃ . In some embodiments, the moiety R &lt; ₃ &gt; is defined herein as defined above but is not H. [

When any of R _A , R _B , and R _C is R ₄ SO ₂ , then R ₄ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₄ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl, or from H, C 1 -C 3 and alkylcyclopropyl. In some embodiments, R ₄ is selected from H and C 1 -C 6 alkyl, for example from H and C 1 -C 4 alkyl, or from H and C 1 -C 3 alkyl, for example from H and CH ₃ , especially CH ₃ . In some embodiments, the moiety R &lt; ₄ &gt; is defined herein as defined above but is not H. [

When any of R _A , R _B , and R _C is R ₅ OC (O), then R ₅ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₅ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl, or from H, C 1 -C 3 and alkylcyclopropyl. In some embodiments, R ₅ is from H and C1-C6 alkyl, for example from from H and C1-C4 alkyl, or H and C1-C3 alkyl, for example, is selected from H and CH _3, in particular H to be.

When either R _A , R _B , and R _C is (R ₆ ON) C (R ₇ ), R ₆ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₆ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl, or from H, C 1 -C 3 and alkylcyclopropyl. In some embodiments, R ₆ is selected from H and C 1 -C 6 alkyl, for example from H and C 1 -C 4 alkyl, or from H and C 1 -C 3 alkyl, for example from H and CH ₃ , especially H to be. R &lt; ₇ &gt; is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl. In some embodiments, R ₇ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl, or from H, C 1 -C 3 and alkylcyclopropyl. In some embodiments, R ₇ is selected from H and C 1 -C 6 alkyl, eg, from H and C 1 -C 4 alkyl, or from H and C 1 -C 3 alkyl, eg, from H and CH ₃ , ₃ . In some embodiments, the moiety R &lt; ₇ &gt; is defined herein as defined above but is not H. In some embodiments, wherein R ₆ is H, R ₇ is as defined above, but defined herein, it is not H, e.g., R ₇ is CH _3.

R _A, R _B, and R _C is, if any one of the R ₈ R ₉ NC (O) or R ₁₀ R ₁₁ N, each of R _8, R _9, R ₁₀ and R ₁₁ are independently H, C1- C6 alkyl and C3-C6 cycloalkyl, for example from H, C1-C4 alkyl and C3-C4 cycloalkyl, or from H, C1-C3 and alkylcyclopropyl. In some embodiments, when any of R _A , R _B , and R _C is R ₈ R ₉ NC (O) or R ₁₀ R ₁₁ N, each of R ₈ , R ₉ , R _10, and R ₁₁ is independently from H and C1-C6 alkyl, for example from from H and C1-C4 alkyl, or H and C1-C3 alkyl, for example, it is selected from H and CH _3.

R _A, R _B, and R _C of any one of the _{R 12 S (O) 2 NR} 13 or R ₁₄ S (O) if the ₂ NR ₁₅ C (O), each of R _12, R _13, R _14, and R ₁₅ is independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, for example from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl, or from H, C 1 -C 3 and alkylcyclopropyl. In some embodiments, when any of R _A , R _B and R _C is R ₁₂ S (O) ₂ NR ₁₃ or R ₁₄ S (O) ₂ NR ₁₅ C (O), each R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from H and C 1 -C 6 alkyl, for example from H and C 1 -C 4 alkyl, or from H and C 1 -C 3 alkyl, for example from H and CH ₃ . In some embodiments, R &lt; ₁₂ &gt; is defined herein as defined above but is not H, and R &lt; ₁₃ &gt; In some embodiments, R &lt; ₁₄ &gt; is defined herein as defined above but is not H, and R &lt; ₁₅ &gt; In some embodiments, R ₁₂ and R ₁₄ are defined herein as defined above, but not H, and R ₁₃ and R ₁₅ are both H.

In some embodiments, R _A, R _B and R _C of any of the one or more R ₁₆ moiety in an optionally substituted phenyl or optionally substituted with one or more R ₁₆ moiety is a 5-or 6-immunogenic heterocycle When it is a reel, the phenyl or heterocyclyl can be substituted with 0, 1, 2 or 3 R ₁₆ moieties, for example 0, 1 or 2 R ₁₆ moieties, or 0 or 1 R ₁₆ moieties such as 1 two R ₁₆ moieties is optionally substituted thienyl.

In some embodiments, R _A, R _B and R _C of any of the one or more R ₁₆ moiety in an optionally substituted phenyl or optionally substituted with one or more R ₁₆ moiety is a 5-or 6-immunogenic heterocycle When it is a reel, it is more specifically a phenyl substituted by 0, 1, 2 or 3 R ₁₆ moieties or a phenyl substituted by 0, 1 or 2 R ₁₆ moieties.

In some embodiments, R _A, R _B and R _C of any of the one or more R ₁₆ moiety in an optionally substituted phenyl or optionally substituted with one or more R ₁₆ moiety is a 5-or 6-immunogenic heterocycle When it is a reel, it is more specifically substituted by 0, 1, 2 or 3 R ₁₆ moieties or, for example, 5- or 6-membered heterocyclyl substituted by 0, 1 or 2 R ₁₆ moieties to be.

In some embodiments, when any of R _A , R _B, and R _C is phenyl substituted with one R ₁₆ moiety, these moieties are located in the para position on the phenyl ring.

In some embodiments, R _A is an optionally substituted 5-or 6-immunogenic heterocyclyl optionally substituted with phenyl or one or more R ₁₆ moiety with one or more R ₁₆ moiety. In some of these embodiments, the compound of formula (I) may be represented by formula (Id).

Wherein ring B is phenyl or 5- or 6-membered heterocyclyl, k is an integer from 0-3 and R ₁₆ , R _B , R _C , W and R _D are defined as hereinbefore defined .

In some embodiments, ring B is phenyl, and the compound of formula (Ic) may be represented by formula (Ie):

Wherein k, R ₁₆ , R _B , R _C , W, and R _D are defined as defined herein.

In some embodiments for compounds of formula (Ie), k is 1 and R &lt; ₁₆ &gt; is para-position, i.e. the compound may be represented by formula (If)

Wherein R ₁₆ , R _B , R _C , W, and R _D are defined as defined herein.

In some embodiments for compounds of formula (Ic), (Id), (Ie) and (If), R _B and R _C are both H.

In some embodiments, when any one of R _A , R _B, and R _C is a 5- or 6-membered heterocyclyl optionally substituted with one or more R ₁₆ moieties, said heterocyclyl is a five membered heterocycle It is a reel. In some embodiments, when any one of R _A , R _B, and R _C is a 5- or 6-membered heterocyclyl optionally substituted with one or more R ₁₆ moieties, the heterocyclyl is 6-membered hetero Lt; / RTI &gt; Any 5- or 6-membered heterocyclyl includes one or more heteroatoms in the ring, for example, 1, 2, 3 or 4 heteroatoms. In some embodiments, the heterocyclyl is aromatic. In some other embodiments, the heterocyclyl is non-aromatic, saturated or unsaturated, for example, the heterocyclyl is a non-aromatic mono-unsaturated form. For example, the heterocyclyl can be selected from the following formula:

When R _A, R _B and R _C of any of the one or more R ₁₆ is a moiety, optionally substituted phenyl or optionally substituted with one or more R ₁₆ moiety is a 5-or 6-immunogenic heterocyclyl, each moiety R ₁₆ is independently halogen, cyano, nitro, R ₁₇ O, R ₁₇ O in an optionally substituted C1-C6 alkyl, R ₁₇ O in an optionally substituted C3-C6-cycloalkyl, R ₁₈ C (O _{), R 19 S, R 20} S (O) 2, R 21 OC (O), (R 22 ON) C (R 23), R 24 R 25 NC (O), R 26 R 27 N, R 28 S (O) ₂ NR ₂₉ , and R ₃₀ S (O) ₂ NR ₃₁ C (O).

In some embodiments, each R ₁₆ is independently halogen, cyano, nitro, R ₁₇ O, R ₁₇ O in an optionally substituted C1-C6 alkyl, R ₁₇ O in an optionally substituted C3-C6 cycloalkyl, , R ₁₉ S, R ₂₀ S (O) ₂ , R ₂₁ OC (O) and R ₂₆ R ₂₇ N.

In some embodiments, each R ₁₆ is independently selected from the group consisting of halogen, cyano, nitro, C 1 -C 6 alkyl optionally substituted with R ₁₇ O, R ₁₇ O, R ₁₉ S, R ₂₀ S (O) ₂ , R ₂₁ OC (O) and R &lt; ₂₆ &gt; R &lt; ₂₇ &gt;

In some embodiments, each R ₁₆ is independently selected from the group consisting of halogen, cyano, nitro, C 1 -C 6 alkyl optionally substituted with R ₁₇ O, R ₁₇ O, R ₁₉ S, R ₂₀ S (O) ₂ , R ₂₁ OC (O), and R &lt; ₂₆ &gt; R &lt; ₂₇ &gt;

In some embodiments, each R ₁₆ is independently R ₁₇ O, R to ₁₇ O with optionally substituted C1-C6 alkyl, and R ₁₇ O substituted with optionally selected from a substituted C3-C6 cycloalkyl, e.g. O R _17, it is selected from optionally substituted C1-C6 alkyl as R ₁₇ O, in particular from R ₁₇ O.

When R ₁₆ is an optionally substituted C1-C6 alkyl as R ₁₇ O, which, for example, R ₁₇ O in an optionally substituted C1-C4 alkyl, such as R ₁₇ O in an optionally substituted C1-C3 alkyl days .

In some embodiments, each R ₁₆ is independently selected from F, Cl, cyano, _{nitro, CH 3, CF 3, (} CH 3) 3 C, CH 3 O, CH 3 S, CH 3 S (O) 2 , COOH, NH ₂ and (CH _{3) 2} is selected from N.

When any R ₁₆ is C 1 -C 6 alkyl optionally substituted with R ₁₇ O, R ₁₇ O or C 3 -C 6 cycloalkyl optionally substituted with R ₁₇ O, the moiety R ₁₇ is H, C 1 -C 6 alkyl or C3-C6 cycloalkyl. In some embodiments, R ₁₇ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl, or from H, C 1 -C 3 and alkylcyclopropyl. In some embodiments, R ₁₇ is selected from H and C 1 -C 6 alkyl, for example, from H and C 1 -C 4 alkyl, or from H and C 1 -C 3 alkyl, for example from H and CH ₃ , to be.

In some other embodiments, the moiety R &lt; ₁₇ &gt; is defined herein as defined above but is not H; For example, R ₁₇ is CH ₃ .

When any R ₁₆ is R ₁₈ C (O), the moiety R ₁₈ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₁₈ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl, or from H, C 1 -C 3 and alkylcyclopropyl. In some embodiments, R ₁₈ is selected from H and C 1 -C 6 alkyl, for example from H and C 1 -C 4 alkyl, or from H and C 1 -C 3 alkyl, for example from H and CH ₃ , especially H to be.

In some other embodiments, the moiety R &lt; ₁₈ &gt; is defined herein as defined above but is not H; For example, R ₁₈ is CH ₃ .

When any R ₁₆ is R ₁₉ S, the moiety R ₁₉ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₁₉ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl, or from H, C 1 -C 3 and alkylcyclopropyl. In some embodiments, R ₁₉ is selected from H and C 1 -C 6 alkyl, for example from H and C 1 -C 4 alkyl, or from H and C 1 -C 3 alkyl, for example from H and CH ₃ , especially H to be.

In some other embodiments, the moiety R ₁₉ is defined herein as defined above but is not H; For example, R ₁₉ is CH ₃ .

When any R ₁₆ is R ₂₀ S (O) ₂ , the moiety R ₂₀ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₂₀ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl, or from H, C 1 -C 3 and alkylcyclopropyl. In some embodiments, R ₂₀ is selected from H and C 1 -C 6 alkyl, for example from H and C 1 -C 4 alkyl, or from H and C 1 -C 3 alkyl, for example from H and CH ₃ , to be.

In some other embodiments, the moiety R ₂₀ is defined herein as defined above but is not H; For example, R ₂₀ is CH ₃ .

When any R ₁₆ is R ₂₁ OC (O), the moiety R ₂₁ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₂₁ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl, or from H, C 1 -C 3 and alkylcyclopropyl. In some embodiments, R ₂₁ is selected from H and C 1 -C 6 alkyl, for example, from H and C 1 -C 4 alkyl, or from H and C 1 -C 3 alkyl, for example from H and CH ₃ , to be.

In some other embodiments, the moiety R ₂₁ is defined herein as defined above but is not H; For example, R ₂₁ is CH ₃ .

When any R ₁₆ is (R ₂₂ ON) C (R ₂₃ ), then R ₂₂ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₂₂ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl, or from H, C 1 -C 3 and alkylcyclopropyl. In some embodiments, R ₂₂ is selected from H and C 1 -C 6 alkyl, for example from H and C 1 -C 4 alkyl, or from H and C 1 -C 3 alkyl, for example from H and CH ₃ , especially H to be. R ₂₃ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₂₃ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl, or from H, C 1 -C 3 and alkylcyclopropyl. In some embodiments, R ₂₃ is selected from H and C 1 -C 6 alkyl, for example from H and C 1 -C 4 alkyl, or from H and C 1 -C 3 alkyl, for example from H and CH ₃ , especially CH ₃ . In some embodiments, the moiety R &lt; ₂₃ &gt; is defined herein as defined above but is not H. In some embodiments, R ₂₂ is H, R ₂₃ is defined herein as defined above, but is not H, for example, R ₂₃ is CH ₃ .

Each R ₂₄ , R ₂₅ , R ₂₆ and R ₂₇ are independently selected from the group consisting of H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, where each R ₁₆ is R ₂₄ R ₂₅ NC (O) or R ₂₆ R ₂₇ N, For example from H, C1-C4alkyl and C3-C4cycloalkyl, or from H, C1-C3 and alkylcyclopropyl. In some embodiments, when any R ₁₆ is R ₂₄ R ₂₅ NC (O) or R ₂₆ R ₂₇ N, each of R ₂₄ , R ₂₅ , R _26, and R ₂₇ is independently H and C 1 -C 6 alkyl from, for example from from H and C1-C4 alkyl, or H and C1-C3 alkyl, for example, it is selected from H and CH _3.

If any of the R ₁₆ is a _{R 28 S (O) 2 NR} 29 or _{R 30 S (O) 2 NR} 31 C (O), each of R _28, R _29, R ₃₀ and R ₃₁ are independently H, C1 From C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, for example from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl, or from H, C 1 -C 3 and alkylcyclopropyl. In some embodiments, any of R ₁₆ is _{R 28 S (O) 2 NR} 29 or R ₃₀ S (O) if the ₂ NR ₃₁ C (O), each of R _28, R _29, R ₃₀ and R ₃₁ It is independently selected from H and C1-C6 alkyl, such as are selected from from H and C1-C4 alkyl, or H and C1-C3 alkyl, such as from H and CH _3. In some embodiments, R &lt; ₂₈ &gt; and R &lt; ₃₀ &gt; are defined herein as defined above but not H, and R ₂₉ and R ₃₁ are both H.

When one of R _A and R _C together with R _B forms a bivalent radical - (CH ₂ ) _m -, where m is an integer from 3 to 5, for example 3 or 4, in particular 3, for example R _B And R _{C form} bi-radical - (CH ₂ ) ₃ .

For example, in some embodiments for compounds of formula (I), one of R _A , R _B, and R _C is H and the other two are independently halogen, cyano, C ₁ -C 4 alkyl, R ₁ O, R ₂ C (O), R ₃ s and R ₄ s (O) selected from the _second, or, or, if adjacent, some embodiments of the remaining two are each the integer by a radical of m is from 3 to 5 with from - (CH ₂ ) _m -.

In some embodiments, one of R _A , R _B and R _C is H and the other two are selected from halogen, cyano, C ₁ -C 4 alkyl and R ₁ O, for example, halogen, For example, from F, Cl, methyl and methoxy; Or halogen and C1-C3 alkyl, such as F, Cl and methyl.

In some embodiments, one of R _A , R _B, and R _C is H and the other two are all selected from halogens, e.g., both are F or Cl, or both are Cl.

In other embodiments, two of R _A , R _B, and R _C are not H and both are selected from C1-C3 alkyl and R ₁ O, e.g., both from methyl and methoxy. In some embodiments, two of R _A , R _B, and R _C are not H and are the same as each other, e.g., both are Cl, or both are methyl, or both are R ₁ O, such as methoxy.

For example, in some embodiments of the compounds of formula (I), for example, from compounds of formula (Ib), R _B and R _C are both halogen, cyano, C1-C4 alkyl and R ₁ O . For example, R _B and R _C can both be selected from halogen, for example, both R _B and R _C are F or Cl, or both R _B and R _C are Cl. In other embodiments, R _B and R _C are both selected from _{C 1} -C 4 alkyl and R ₁ O, for example, both R _B and R _C are selected from methyl and methoxy, for example, both are methyl. In the compounds of formula (I), for example, in the compounds of formula (Ib), R _B and R _C may be different from each other or may be the same as each other.

In the compounds of formula (I), the linking moiety W is a direct bond or X ₁ -X ₂ -X ₃ . In some embodiments, W is a direct bond, i.e., the compound can be represented by formula (Ig):

Wherein R _A , R _B , R _C and R _D are defined as defined herein.

In some other embodiments, W is X ₁ -X ₂ -X ₃ , and the compound can be represented by formula (Ih):

Wherein R _A , R _B , R _C , R _D , X ₁ , X ₂ and X ₃ are defined as defined herein.

In the compounds of formula (Ih)

X ₁ is C ₁ -C 2 alkylene and C ₁ -C 2 alkylene is optionally substituted with C 1 -C 4 alkyl or R ₃₂ O;

X ₂ is O or is omitted; And

X ₃ is a direct bond or C 1 -C 2 alkylene, and C 1 -C 2 alkylene is optionally substituted with C 1 -C 4 alkyl or R ₃₂ O.

In some embodiments, X ₁ is C ₁ -C 2 alkylene optionally substituted by C ₁ -C 4 alkyl, for example, X ₁ is C ₁ alkylene optionally substituted by C ₁ -C 4 alkyl.

In some embodiments, X ₁ is an optionally substituted, C1 alkylene substituted by R ₃₂ O, or C1-C4 alkyl. In some embodiments, X ₁ is C ₁ -C 2 alkylene, for example, X ₁ is C ₁ alkylene (ie, CH ₂ ).

The moiety X ₂ is omitted or O. In some embodiments, X &lt; _{2 &gt;} is omitted, and thus this compound can be represented by formula (Ij)

Wherein R _A , R _B , R _C , R _D , X ₁ and X ₃ are defined as defined herein.

Expression in the compounds of (Ij), X ₁ is a C1-C2 alkylene with, C1-C2 alkylene group is optionally substituted with C1-C4 alkyl, or R ₃₂ O, X ₃ is a direct bond or a C1-C2 alkylene , C1-C2 alkylene group is optionally substituted with C1-C4 alkyl, or R ₃₂ O; For example, X ₁ is C 1 -C 2 alkylene optionally substituted with R ₃₂ O or C 1 -C 4 alkyl, X ₃ is a direct bond or C 1 -C 2 alkylene, for example, X ₃ is C ₁ -C 2 Alkyl, or X &lt; ₃ &gt; is C1 alkylene.

In some other embodiments for formula (Ij), X ₁ is C 1 -C 2 alkylene optionally substituted by R ₃₂ O or C 1 -C 4 alkyl, and X ₃ is a direct bond or C 1 alkylene.

In some other embodiments of formula (Ij), X ₁ is C 1 -C 2 alkylene optionally substituted with R ₃₂ O or C 1 -C 4 alkyl, and X ₃ is a direct bond.

Expression in some other implementation of the (Ij) Compound example, X ₁ is an optionally substituted C1 alkylene with R ₃₂ O or C1-C4 alkyl, X ₃ is directly bonded, or R ₃₂ O, or C1-C4 alkyl Optionally substituted C1-C2 alkylene; For example, X ₁ is C ₁ alkylene optionally substituted with R ₃₂ O or C 1 -C 4 alkyl, and X ₃ is a direct bond or C 1 -C 2 alkylene.

In some other embodiments, X ₂ is O, and thus the present compounds may be represented by formula (Ik):

Wherein R _A , R _B , R _C , R _D , X ₁ and X ₃ are defined as defined herein.

The moiety X ₃ is a direct bond or a C 1 -C 2 alkylene optionally substituted with R ₃₂ O or C 1 -C 4 alkyl. In some embodiments, X &lt; ₃ &gt; is a direct bond or C1 alkylene optionally substituted with R &lt; ₃₂ &gt; O or C1-C4 alkyl. In some embodiments, X ₃ is a direct bond or C1 alkylene. In some embodiments, X ₃ is a direct bond, and therefore the compound of formula (Ih) can be represented by formula (Im):

Wherein R _A , R _B , R _C , R _D , X ₁ and X ₂ are defined as defined herein.

In some embodiments for compounds of formula (Im), X &lt; ₂ &gt; In some other embodiments for compounds of formula (Im), X ₂ is omitted, and thus the present compounds can be represented by formula (In):

Wherein R _A , R _B , R _C , R _D and X ₁ are defined as defined herein.

When either X ₁ or X ₃ , or both X ₁ and X ₃ are substituted with a moiety selected from C 1 -C 4 alkyl or R ₃₂ O, the moiety is more specifically a C 1 -C 3 alkyl and R ₃₂ O, or from C 1 -C 2 alkyl and R ₃₂ O, especially CH ₃ and R ₃₂ O. In some embodiments, the moiety is selected from C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, or CH _3. In some embodiments, X ₁ and X ₃ are not both substituted. In some embodiments, the moiety is R &lt; ₃₂ &gt; O.

The moiety R ₃₂ is H and C 1 -C 4 alkyl. In some embodiments, R ₃₂ is selected from H and C 1 -C 3 alkyl, or from H and C 1 -C 2 alkyl, especially from H and CH ₃ , for example, H. In some other embodiments, R ₃₂ is selected from C 1 -C 4 alkyl, such as C 1 -C 3 alkyl, or C 1 -C 2 alkyl, especially CH ₃ .

In some embodiments, W is a _{bond, CH 2, CH 2 CH 2} , CH 2 CH 2 CH 2, CH (CH 3), CH (CH 3) CH 2, CH (OH), CH (OCH 3) , CH (CH ₃₎ O or CH (CH ₃₎ OCH _2, and; For example, W is a direct bond, CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ , CH (CH ₃ ), CH (CH ₃ ) CH ₂ , CH (OH) or CH (OCH ₃ ).

In some embodiments, W is a direct bond, CH ₂ , CH ₂ CH ₂ or CH ₂ CH ₂ CH ₂ , for example W is CH ₂ CH ₂ or CH ₂ CH ₂ CH ₂ , W is CH ₂ CH _{2 .}

In some embodiments, W is a direct bond, CH ₂ or CH ₂ CH ₂ , for example W is a direct bond or CH ₂ , for example W is CH ₂ .

In some other embodiments, W is _{CH 2 CH 2, CH 2 CH} 2 CH 2, CH (CH 3), CH (CH 3) CH 2, CH (OH), CH (OCH 3), CH (CH 3 ) is O or CH (CH ₃₎ OCH _2.

In the compounds of formula (I), the moiety R _D is C1-C6 alkyl or a cyclic moiety selected from phenyl, 4- to 6-membered heterocyclyl, C4-C6 cycloalkyl and C5-C6 cycloalkenyl Wherein the cyclic moiety is optionally substituted with one or more R ₃₃ ; For example, the moiety R _D is C1-C6 alkyl, or is a cyclic moiety selected from phenyl, 4- to 6-membered heterocyclyl and C4-C6 cycloalkyl, wherein the cyclic moiety is one or more R &lt; ₃₃ &gt;

When R _D is C 1 -C 6 alkyl, it may be selected, for example, from C 3 -C 6 alkyl, or from C 3 -C 5 alkyl. In some embodiments, when R _D is C 1 -C 6 alkyl, W is a direct bond.

In some embodiments, the moiety R _D is a cyclic moiety selected from phenyl, 4- to 6-membered heterocyclyl, C 4 -C 6 cycloalkyl and C 5 -C 6 cycloalkenyl, such as phenyl, 4 To 6-membered heterocyclyl and C4-C6 cycloalkyl, which cyclic moiety is optionally substituted with one or more R &lt; ₃₃ &gt; In some embodiments, the compound of formula (I) may be represented by formula (Io)

Wherein R, R _A, R _B, R _C, W and R ₃₃ are defined as defined herein, ring A is phenyl, 4-to 6-immunogenic heterocyclyl, C4-C6 cycloalkyl or C5-C6 Cycloalkenyl, and n is an integer of 0 to 3.

In compounds of formula (Io), ring A is substituted with n R ₃₃ moieties, wherein n is an integer from 0 to 3. In some embodiments, n is an integer from 0 to 2, e.g., n is 0, 1, or 2, or n is 1 or 2. In some embodiments, n is zero. In other embodiments, n is 1. In another embodiment, n is 2 or 3, for example, n is 2.

In compounds of formula (Io), each moiety R ₃₃ is independently selected from the group consisting of halogen, cyano, C 1 -C 6 alkyl optionally substituted with R ₃₄ O, C 3 -C 6 cycloalkyl, phenyl, 5- or 6- _{heterocyclyl, R 34 O, R 35 OC} (O), R 36 S (O) 2, R 37 C (O), R 38 R 39 N, R 40 R is selected from ₄₁ N (CO); When n is 2 or greater, two R &lt; ₃₃ &gt; groups bonded to one and the same carbon atom may form a 4- to 6-membered ring optionally including one or more heteroatoms in the ring with the carbon atoms to which they are both attached, For example, two R ₃₃ bound to one and the same carbon atom may form a bivalent radical -CH ₂ -L-CH ₂ -, wherein L is CH ₂ , NH or O, for example, L is NH .

In some embodiments, each moiety R ₃₃ is independently selected from halogen, cyano, C 1 -C 6 alkyl optionally substituted with R ₃₄ O, C 3 -C 6 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl, R ₃₄ O, R ₃₅ OC (O), R ₃₆ S (O) ₂ , R ₃₇ C (O), R ₃₈ R ₃₉ N, R ₄₀ R ₄₁ N (CO); For example, each moiety R ₃₃ is independently selected from the group consisting of halogen, cyano, C 1 -C 6 alkyl optionally substituted with R ₃₄ O, C 3 -C 6 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl, R ₃₄ O, R ₃₆ S (O) ₂ , R ₃₇ C (O), R ₃₈ R ₃₉ N and R ₄₀ R ₄₁ N (CO).

In some other embodiments, when n is 2 or 3, for example, when n is 2, two R &lt; ₃₃ &gt; groups bonded to one and the same carbon atom, together with the carbon atoms to which they are both attached, heteroatom may optionally form a 4- to 6-ring containing the immunogenic character, and for example, the two R ₃₃ bonded to one and the same carbon atom of the, L is CH _2, O or NH is, for example L NH, by radicals -CH ₂ -L-CH ₂ -.

When the moiety R ₃₃ is halogen, this halogen may be F, Cl or Br, in particular F or Cl.

When the moiety R ₃₃ is C 1 -C 6 alkyl optionally substituted with R ₃₄ O, said C 1 -C 6 alkyl may especially be C 1 -C 4 alkyl, more particularly C 1 -C 3 alkyl, such as methyl or ethyl have.

In some embodiments, when the moiety R ₃₃ is C 1 -C 6 alkyl optionally substituted with R ₃₄ O, it is more specifically not substituted with any R ₃₄ O, that is, R ₃₃ is C 1 -C 6 Alkyl, C1-C4 alkyl or C1-C3 alkyl, such as methyl or ethyl.

In some embodiments for compounds of formula (Io), when the moiety R ₃₃ is C 1 -C 6 alkyl optionally substituted with R ₃₄ O, it may be, for example, a compound of formula R ₃₄ O (CH ₂ ) _p Where p is an integer from 1 to 3, for example, p is 1 or 2, or p is 1.

In moiety R ₃₄ O, R ₃₄ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; Wherein alkyl or cycloalkyl is optionally substituted by R &lt; ₄₂ &gt; O. In some embodiments, R ₃₄ is H, C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted by R ₄₂ O. In some embodiments, R ₃₄ is H or C 1 -C 6 alkyl, wherein said alkyl is optionally substituted by R ₄₂ O, for example, R ₃₄ is H or C 1 -C 3 alkyl, wherein said alkyl is R ₄₂ O. &lt; / RTI &gt; In some embodiments, R ₃₄ is H, CH ₃ , CH ₃ CH ₂ , CF ₃ CH _2, or CH ₃ OCH ₂ CH ₂ .

In the moiety R ₃₅ OC (O), R ₃₅ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₃₅ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl, or from H, C 1 -C 3 and alkylcyclopropyl. In some embodiments, R ₃₅ is from H and C1-C6 alkyl, such as H and is selected from from C1-C4 alkyl, or H and C1-C3 alkyl, such as from H and CH _3, in particular CH ₃ . In some embodiments, the moiety R ₃₅ is defined herein as defined above but is not H.

In the moiety R ₃₆ S (O) ₂ , R ₃₆ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₃₆ is selected from H, C 1 -C 4 alkyl, and C 4 -C 6 cycloalkyl, or from H, C 1 -C 3, and alkylcyclo-pentyl. In some embodiments, R ₃₆ is selected from H and C 1 -C 6 alkyl, for example, from H and C 1 -C 4 alkyl, or from H and C 1 -C 3 alkyl, for example, H, CH ₃ , CH ₃ CH ₂ . In some embodiments, the moiety R ₃₆ is defined herein as defined above but is not H, for example, R ₃₆ is methyl, ethyl or cyclopentyl.

In the moiety R ₃₇ C (O), R ₃₇ is selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted by R ₄₃ O. In some embodiments, R ₃₇ is selected from C 1 -C 5 alkyl and C 4 -C 6 cycloalkyl, or from C 1 -C 4 alkyl and C 4 -C 5 cycloalkyl, for example, CH ₃ , CF ₃ CH ₂ , (CH ₃ ) ₂ CHCH &lt; ₃ &gt; or cyclopentyl. In some embodiments, R ₃₇ is selected from C 1 -C 6 alkyl optionally substituted by R ₄₃ O, and C 3 -C 6 cycloalkyl. When C1-C6 alkyl is substituted by R &lt; ₄₃ &gt; O, such alkyl may be, for example, C1-C4 alkyl or C1-C3 alkyl, such as methyl.

In the moiety R ₃₈ R ₃₉ N, R ₃₈ and R ₃₉ are independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is R ₄₄ R ₄₅ N or R ₄₆ O Or &lt; RTI ID = 0.0 &gt;

R ₃₈ and R ₃₉ is optionally substituted with with the nitrogen atom to which both they, optionally including the at least one other heteroatom in, and C1-C6 alkyl, e.g., C1-C3 alkyl or C1-C2 alkyl, such as CH ₃ To form a 4- to 6-membered heterocyclic ring.

In some embodiments, R ₃₈ and R ₃₉ are independently selected from H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted by R ₄₄ R ₄₅ N or R ₄₆ O Substituted; For example, R ₃₈ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl; For example, H and C1-C3 alkyl is selected from H and CH _3, R ₃₉ is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein said alkyl or cycloalkyl is R ₄₄ R ₄₅ N or R &lt; ₄₆ &gt; O.

In some embodiments, R ₃₈ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl; For example, is selected from H and C1-C3 alkyl, such as H and CH _3, for example, H; R ₃₉ is selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted by R ₄₄ R ₄₅ N or R ₄₆ O; Or R &lt; ₃₈ &gt; and R &lt; ₃₉ &gt;, together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocyclic ring optionally containing one or more other heteroatoms and being substituted by C1-C6 alkyl such as C1- - form a heterocyclic ring; For example, R ₃₈ and R ₃₉ , together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocyclic ring optionally comprising one or more other heteroatoms, or R ₃₈ and R _39, Together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring which does not contain another heteroatom, for example azetidinyl.

In some embodiments, R ₃₈ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl; For example, from H and C1-C3 alkyl, for example, is selected from H and CH _3, H is an example; And R ₃₉ is selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, or R ₃₈ and R ₃₉ together with the nitrogen atom to which they are attached, optionally comprise one or more other heteroatoms and are selected from C 1 -C 6 alkyl, the example optionally substituted with C1-C3 alkyl, C1-C2 alkyl, or CH _3, 4- to 6-immunogenic form a heterocyclic ring; For example, R ₃₈ and R ₃₉ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring optionally comprising one or more other heteroatoms, or R ₃₈ and R ₃₉ together form a 4- Together with the nitrogen atom, form a 4- to 6-membered heterocyclic ring which does not contain another heteroatom. For example, R ₃₈ R ₃₉ N can be selected from the following formulas:

.

.

In some embodiments, R ₃₈ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl; For example, from H and C1-C3 alkyl, for example it is selected from H and CH _3, for example, H; R ₃₉ is selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is substituted by R ₄₄ R ₄₅ N or R ₄₆ O; For example NR &lt; ₃₈ &gt; R &lt; ₃₉ &gt;

In the above formula, R ₃₈ is defined herein as defined above, for example, R ₃₈ is H or C 1 -C 3 alkyl, especially R ₃₈ is H or CH ₃ .

In some embodiments, when R ₃₉ is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl optionally substituted by R ₄₄ R ₄₅ N or R ₄₆ O, R ₃₉ is more particularly R ₄₄ R ₄₅ N or R ₄₆ O, optionally substituted C1-C6 alkyl by, for example, R ₄₄ R ₄₅ N, optionally substituted C1-C6 alkyl by, for example, R ₄₄ R a by ₄₅ N, optionally substituted C1-C4 or R &lt; ₄₄ &gt; R &lt; ₄₅ &gt; N.

In some other embodiments, when R ₃₉ is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl optionally substituted by R ₄₄ R ₄₅ N or R ₄₆ O, R ₃₉ is more particularly R ₄₆ O in the optionally substituted C1-C6 alkyl, such as a C1-C3 alkyl, optionally substituted by R ₄₆ O, optionally substituted with C1-C4 alkyl, or R ₄₆ O.

In some embodiments, R ₃₈ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl; For example, from H and C1-C3 alkyl, for example, it is selected from H and CH _3, for example, H; R ₃₉ is selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, for example from H and C 1 -C 6 alkyl, wherein said alkyl or cycloalkyl is substituted by R ₄₄ R ₄₅ N.

In some embodiments, R ₃₈ is selected from H, C 1 -C 4 alkyl, and C 3 -C 4 cycloalkyl; For example, from H and C1-C3 alkyl, for example selected from H and CH _3, for example, H; R ₃₉ is selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is substituted by R ₄₆ O.

In the moiety R ₄₀ R ₄₁ NC (O), R ₄₀ and R ₄₁ are independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is R ₄₇ R ₄₈ N or R ₄₉ or by the O optionally substituted, or R ₄₀ and R ₄₁ are optionally includes the one or more other heteroatoms together with the nitrogen atom to which they are attached, and optionally substituted by C1-C6-alkyl, 4- to 6-immunogenic heterocyclic To form a click ring.

In some embodiments, R ₄₀ and R ₄₁ are independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted by R ₄₇ R ₄₈ N or R ₄₉ O Substituted; For example, R ₄₀ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl; For example, the R ₄₇ from H and C1-C3 alkyl, for example, is selected from H and CH _3, R ₄₁ is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein said alkyl or cycloalkyl R &lt; ₄₈ &gt; N or R &lt; ₄₉ &gt; O.

In some embodiments, R ₄₀ is selected from H, C 1 -C 4 alkyl, and C 3 -C 4 cycloalkyl; For example, H and C1-C3 alkyl, for example is selected from H and CH _3, for example, H; R ₄₁ is selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted by R ₄₇ R ₄₈ N or R ₄₉ O; Or R ₄₀ and R ₄₁ include those optionally one or more other heteroatoms together with the nitrogen atom to which they are attached, and optionally substituted with, for example, C1-C3 alkyl, C1-C2 alkyl, or CH ₃ optionally substituted with C1-C6 alkyl Or a 4- to 6-membered heterocyclic ring, wherein R ₄₀ and R ₄₁ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring containing no additional heteroatoms, Form azetidinyl.

In some embodiments, R ₄₀ is selected from H, C 1 -C 4 alkyl and C 3 -C 4 cycloalkyl; For example, from H and C1-C3 alkyl, for example selected from H and CH _3, for example, H; R ₄₁ is selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, or R ₄₀ and R ₄₁ together with the nitrogen atom to which they are attached, optionally comprise one or more other heteroatoms and are optionally substituted by C 1 -C 6 alkyl, C1-C3 alkyl, C1-C2 substituted alkyl, or CH _3, 4- to 6-immunogenic or to form a heterocyclic ring; For example, R ₄₀ and R ₄₁ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring which does not contain additional heteroatoms.

In some embodiments, R ₄₀ is selected from H, C 1 -C 4 alkyl, and C 3 -C 4 cycloalkyl; For example, from H and C1-C3 alkyl, for example it is selected from H and CH _3, for example, H; R ₄₁ is selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is substituted with R ₄₇ R ₄₈ N or R ₄₉ O; For example, R ₄₀ R ₄₁ NC (O) is selected from the following formula:

.

.

Wherein, R ₄₀ is defined as previously defined herein, e.g., R ₄₀ is H or C1-C3 alkyl, in particular R ₄₀ is H or CH _3.

In some embodiments, when R ₄₁ is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl optionally substituted by R ₄₇ R ₄₈ N or R ₄₉ O, R ₄₁ is more particularly R ₄₇ R ₄₈ N or R ₄₉ O in an optionally substituted C1-C6 alkyl, such as R optionally substituted C1-C6 alkyl, substituted with ₄₇ R ₄₈ N, for example R ₄₇ R ₄₈ N and optionally substituted C1-C4 alkyl, or R ₄₇ Lt; ₄₈ &gt; N.

In some other embodiments, when R ₄₁ is R ₄₇ R ₄₈ N or an optionally substituted C1-C6 alkyl or C3-C6 cycloalkyl by R ₄₉ O, R ₄₁ is more specifically selective to the R ₄₉ O with a substituted C1-C6 alkyl such as optionally substituted C1-C3 alkyl optionally substituted with C1-C4 alkyl, or R ₄₉ O substituted with R ₄₉ O.

In some embodiments, R ₄₀ is selected from H, C 1 -C 4 alkyl, and C 3 -C 4 cycloalkyl; For example, from H and C1-C3 alkyl, for example selected from H and CH _3, for example, H; R ₄₁ is selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, for example, from H and C 1 -C 6 alkyl, wherein said alkyl or cycloalkyl is substituted with R ₄₇ R ₄₈ N.

In some embodiments, R ₄₀ is selected from H, C 1 -C 4 alkyl, and C 3 -C 4 cycloalkyl; For example, from H and C1-C3 alkyl, for example selected from H and CH _3, for example, H; R ₄₁ is selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is substituted with R ₄₉ O.

In moieties R ₄₂ O, R ₄₃ O, R ₄₆ O and R ₄₉ O, R ₄₂ , R ₄₃ , R ₄₆ and R ₄₉ are independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl. In some embodiments, each of R ₄₂ , R ₄₃ , R ₄₆ and R ₄₉ are selected from H and C 1 -C 6 alkyl, for example from H and C 1 -C 3 alkyl, or from H and C 1 -C 2 alkyl, for example from H and CH ₃ .

In R ₄₂ O, R ₄₂ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₄₂ is H, C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl, for example, H, C 1 -C 3 alkyl or cyclopropyl. In some embodiments, R ₄₂ is H or C 1 -C 6 alkyl, for example, R ₄₂ is H or C 1 -C 3 alkyl. In some embodiments, R ₄₂ is H or CH ₃ .

In the moiety R ₄₃ O, R ₄₃ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₄₃ is H, C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl, such as H, C 1 -C 3 alkyl or cyclopropyl. In some embodiments, R ₄₃ is H or C 1 -C 6 alkyl, for example R ₄₃ is H or C 1 -C 3 alkyl. In some embodiments, R ₄₃ is H or CH ₃ .

In moiety R ₄₆ O, R ₄₆ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₄₆ is H, C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl, for example, H, C 1 -C 3 alkyl or cyclopropyl. In some embodiments, R ₄₆ is H or C 1 -C 6 alkyl, for example, R ₄₆ is H or C 1 -C 3 alkyl. In some embodiments, R ₄₆ is H or CH ₃ .

In the moiety R ₄₉ O, R ₄₉ is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl. In some embodiments, R ₄₉ is H, C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl, for example, H, C 1 -C 3 alkyl or cyclopropyl. In some embodiments, R ₄₉ is H or C 1 -C 6 alkyl, for example, R ₄₉ is H or C 1 -C 3 alkyl. In some embodiments, R ₄₉ is H or CH ₃ .

In the compounds of formula (Io), ring A is C4-C6 cycloalkyl, C5-C6 cycloalkenyl, phenyl or 4- to 6-membered heterocyclyl. In some embodiments, ring A is C4-C6 cycloalkyl, for example ring A is C5-C6 cycloalkyl.

In embodiments wherein ring A is phenyl, the compound of formula (Io) may be represented by formula (Ip): &lt; EMI ID =

Wherein R _A , R _B , R _C , R ₃₃ , n and W are defined as hereinbefore defined.

In the compounds of formula (Ip), n is an integer from 0 to 3. In some embodiments for compounds of formula (Ip), n is an integer from 0 to 2, for example, n is 0, 1 or 2.

In compounds of formula (Ip), each R ₃₃ is independently selected from the group consisting of halogen, cyano, C 1 -C 6 alkyl optionally substituted with R ₃₄ O, C 3 -C 6 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl , R ₃₄ O, R ₃₅ OC (O), R ₃₆ S (O) ₂ , R ₃₇ C (O), R ₃₈ R ₃₉ N and R ₄₀ R ₄₁ N (CO).

In some embodiments for compounds of formula (Ip), each R ₃₃ is independently selected from the group consisting of halogen, cyano, C 1 -C 6 alkyl optionally substituted with R ₃₄ O, phenyl, 5- or 6-membered heterocyclyl , R ₃₄ O, R ₃₅ OC (O), R ₃₆ S (O) ₂ , R ₃₇ C (O), R ₃₈ R ₃₉ N and R ₄₀ R ₄₁ N (CO).

In some embodiments for compounds of formula (Ip), each R ₃₃ is independently selected from halogen, cyano, phenyl, C 1 -C 6 alkyl optionally substituted with R ₃₄ O, R ₃₆ S (O) ₂ and R ₃₈ R ₃₉ N. &lt; / RTI &gt; In some embodiments, each R ₃₃ is independently selected from halogen, cyano, C 1 -C 6 alkyl optionally substituted with R ₃₄ O, R ₃₄ O, R ₃₆ S (O) ₂ and R ₃₈ R ₃₉ N do. In some embodiments, each R ₃₃ is independently selected from halogen, cyano, and C 1 -C 6 alkyl optionally substituted with R ₃₄ O. In some embodiments, each R ₃₃ is halogen, e.g., R ₃₃ is independently selected from F, Cl, and Br, especially selected from F and Cl.

Expression In some implementations of the compounds of (Ip) for example, if R ₃₃ is a C1-C6 alkyl, or R ₃₄ O is substituted by R ₃₄ O, R ₃₃ can be represented by R ₃₄ O (CH _{2) p} and , Wherein p is an integer from 0 to 3, and R ₃₄ is H or C 1 -C 4 alkyl, more particularly C 1 -C 3 alkyl, especially methyl. In this embodiment, the integer p may be selected more specifically from 0 to 2, for example, p is 0. In some particular embodiments for compounds of formula (Ip), any R ₃₄ O (CH ₂ ) _p is C1-C4 alkoxy, such as C1-C3 alkoxy, especially methoxy.

In some embodiments for compounds of formula (Ip), when R ₃₃ is R ₃₆ S (O) ₂ , R ₃₆ is H or C 1 -C 4 alkyl, and more specifically may be selected from C 1 -C 4 alkyl For example, R ₃₆ is C 1 -C 3 alkyl, especially R ₃₆ is methyl. Thus, in some specific embodiments of compounds of formula (Ip), any R ₃₆ S (O) ₂ is CH ₃ (SO) ₂ .

In some embodiments for compounds of formula (Ip), at least one R ₃₃ is R ₃₈ R ₃₉ N, wherein R ₃₈ and R ₃₉ are defined herein as defined above. In some of these embodiments, R ₃₈ is H or C 1 -C 4 alkyl; R ₃₉ is H, C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl optionally substituted with a moiety selected from R ₄₆ O and R ₄₄ R ₄₅ N; R ₄₄ , R ₄₅ and R ₄₆ are independently selected from H and C 1 -C 4 alkyl; Or R ₃₈ and R ₃₉ together form a bi-radical - (CH ₂ ) _s - wherein s is an integer from 3 to 5. In some of these embodiments, R ₃₈ is H and R ₃₉ is C 1 -C 4 alkyl optionally substituted with a moiety selected from R ₄₄ R ₄₅ N and R ₄₆ O; In particular, R ₃₈ is H and R ₃₉ is C 1 -C 4 alkyl optionally substituted with R ₄₆ O. In some embodiments of the compounds of formula (Ip), and any of R ₃₈ R ₃₉ N is NHR _39, wherein R ₃₉ is defined as defined herein, specifically it is substituted with R ₄₆ O C1- and C4 alkyl, for example, R ₃₈ R ₃₉ N is _{NH (CH 2 CH 2 OCH 3} ).

In compounds of formula (Ip), W is defined herein as defined above. In some embodiments, W is a direct bond and therefore a compound of formula (Ip) may be represented by formula (Iq).

Wherein R _A, R _B , R _C , n and R ₃₃ are defined as defined herein.

In some embodiments of the compounds of formula (Ip), W is C1-C4 alkyl, e.g., C1-C3 alkyl, especially an optionally substituted C1-C3 alkylene substituted with methyl or R ₃₂ O, where R ₃₂ is H or C1-C4 alkyl, or is H or C1-C3 alkyl, especially H or methyl.

In some embodiments for compounds of formula (Ip), W is a direct bond, CH ₂ , CH ₂ CH ₂ , CH (CH ₃ ), CH (OH) or CH (OCH ₃ ).

In some embodiments of compounds of formula &lt; RTI ID = 0.0 &gt; (Ip)

R _A , R _B and R _C are independently selected from H, halogen, C ₁ -C 4 alkyl and R ₁ O;

R &lt; ₁ &gt; is C1-C4 alkyl;

W is either a bond, or R ₃₂ with O or C1-C4 alkyl optionally substituted, C1-C3 alkylene;

R ₃₂ is H or C 1 -C 4 alkyl;

n is an integer from 0 to 3;

Each R ₃₃ is independently selected from halogen, cyano, phenyl, R ₃₄ O (CH ₂ ) _p , R ₃₆ S (O) ₂ and R ₃₈ R ₃₉ N;

R &lt; ₃₄ &gt; is C1-C4 alkyl;

p is 0;

_R36 is C1-C4 alkyl;

R ₃₈ is H;

R ₃₉ is C 1 -C 4 alkyl substituted with R ₄₆ O; And

R &lt; ₄₆ &gt; is C1-C4 alkyl.

In some embodiments for compounds of formula (Io), ring A is a 5- or 6-membered heterocyclyl which may be saturated or unsaturated, aromatic or non-aromatic. In some embodiments, ring A is a 5- or 6-membered heteroaryl. In some cases for these embodiments, the number n of the moiety R ₃₃ on ring A is 0 to 2, especially 0 or 1, and more particularly n is 1.

In some embodiments, when ring A is 5- to 6-membered heteroaryl, any R ₃₃ is independently selected from the group consisting of halogen, C 1 -C 4 alkyl optionally substituted by R ₃₄ O, C 3 -C 6 cycloalkyl, R ₃₇ C (O), R ₃₈ R ₃₉ N, and R ₄₀ R ₄₁ N (CO).

In another embodiment, when the ring A is a 5- to 6-immunogenic heteroaryl, any of R ₃₃ is independently optionally substituted by halogen, C1-C4 alkyl, C3-C6-cycloalkyl, R ₃₄ O C1- C4 is selected from _{alkyl, R 37 C (O),} R 38 R 39 N , and _{R 40 R 41 N (CO)} .

In some embodiments, when ring A is 5- to 6-membered heteroaryl, any R ₃₃ is independently selected from halogen, C 1 -C 4 alkyl optionally substituted with R ₃₄ O, and R ₃₈ R ₃₉ N .

In certain embodiments, when ring A is 5- to 6-membered heteroaryl, any R ₃₃ is R ₃₈ R ₃₉ N.

For example, in some embodiments, ring A is 5- to 6-membered heteroaryl, n is 1, R ₃₃ is halogen, C 1 -C 4 alkyl optionally substituted with R ₃₄ O, or R ₃₈ R ₃₉ N; Especially R ₃₈ R ₃₉ N.

In some embodiments, Ring A is a 5-or 6-immunogenic heteroaryl, n is 1, R ₃₃ is R ₃₈ and R ₃₉ N, wherein R ₃₈ is H, R ₃₉ is a C1 substituted with R ₄₆ O -C4 alkyl; R &lt; ₄₆ &gt; is C1-C4 alkyl.

In some embodiments, when ring A is a 5- or 6-membered heteroaryl,

R _A, R _B and R _C are independently selected from H, halogen, cyano, C 1 -C 4 alkyl, and R ₂ C (O); For example, H, are selected from halogen, C1-C4 alkyl, and R ₂ C (O);

W is a direct bond or C1-C3 alkylene;

n is 0 or 1;

Each R ₃₃ is independently selected from the group consisting of halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkyl optionally substituted with R ₃₄ O, R ₃₇ C (O), R ₃₈ R ₃₉ N and R ₄₀ R ₄₁ N (CO);

R ₃₄ is H or C 1 -C 4 alkyl;

R &lt; ₃₈ &gt; is H or C1-C4 alkyl; R ₃₉ is C 3 -C 6 cycloalkyl or C 1 -C 4 alkyl optionally substituted with a moiety selected from R ₄₄ R ₄₅ N and R ₄₆ O; Or R ₃₈ and R ₃₉ together form a bi-radical - (CH ₂ ) _s - wherein s is an integer from 3 to 5;

R &lt; ₄₀ &gt; is H or C1-C4 alkyl;

R ₄₁ is C 1 -C 4 alkyl substituted with R ₄₉ O;

R ₄₄ , R ₄₅ and R ₄₆ are independently H and C 1 -C 4 alkyl; And

R ₄₉ is C 1 -C 4 alkyl.

In certain embodiments, when ring A is 5- to 6-membered heteroaryl, it is more particularly a 5-membered heteroaryl. In some embodiments, when ring A is a 5-membered heteroaryl, it is more specifically a thiazolyl, especially a 1,3-thiazolyl.

In some embodiments, the present compounds may be represented by formula (Ir)

Wherein R _A, R _B , R _C , R ₃₃ , W, and n are defined as defined herein.

In some embodiments for compounds of formula (Ir), W is a direct bond. In some embodiments for compounds of formula (Ir), n is 1. In some embodiments for compounds of formula (Ir), ring A is 1,3-thiazol-4-yl.

In some embodiments for compounds of formula (Ir), ring A is 1,3-thiazol-4-yl and n is 1. In some embodiments, when ring A is 1,3-thiazol-4-yl and n is 1, R ₃₃ is at position 2, and therefore the compound of formula (I) Can be displayed:

Wherein R _A, R _B , R _C , R _33, and W are defined as defined herein.

In some particular embodiments of compounds of formula (Is), R ₃₃ is selected from halogen, such as Br, R ₃₄ O and R ₃₈ R ₃₉ N, for example selected from halogen and R ₃₈ R ₃₉ N , Especially R ₃₈ R ₃₉ N. More specifically, R ₃₃ is R ₃₈ R ₃₉ N, wherein R ₃₈ is H or C 1 -C 3 alkyl, such as H or methyl, especially H, and R ₃₉ is optionally substituted with C 3 -C 6 cycloalkyl or R ₄₆ O Substituted C1-C4 alkyl, and R &lt; ₄₆ &gt; is C1-C4 alkyl. In some embodiments, the compound is represented by the formula (It):

Wherein R _A, R _B , R _C , W, R ₃₈ and R ₄₆ are defined as defined herein.

In some embodiments of compounds of formula (Io), when ring A is a 5-membered heteroaryl, such as thiazolyl,

R _A, R _B and R _C are independently selected from H, halogen, cyano, C 1 -C 6 alkyl, R ₂ C (O), or phenyl optionally substituted with one or more R ₁₆ moieties; For example, from H, halogen, cyano, C1-C6 alkyl and R ₂ C (O); Or H, halogen, C1-C4 alkyl and R is selected from ₂ C (O);

W is a direct bond;

n is 0 or 1;

R ₃₃ is halogen, R ₃₄ O, or R ₃₈ R ₃₉ N, such as halogen or R ₃₈ R ₃₉ N;

R ₃₈ is H;

R ₃₉ is C 1 -C 4 alkyl optionally substituted with R ₄₆ O, or C 3 -C 6 cycloalkyl, for example, C 1 -C 4 alkyl substituted with R ₄₆ O; And

R &lt; ₄₆ &gt; is C1-C4 alkyl.

In certain other particular embodiments, when ring A is a 5- or 6-membered heteroaryl, more specifically it refers to a 6-membered heteroaryl, e.g., one or two heteroatoms in the ring, such as 1 or Is a six-membered heteroaryl comprising two N, for example ring A is pyrimidinyl or pyridinyl, especially pyridinyl. When ring A is pyridinyl, the compound of formula (I) may be represented by formula (Iu).

Wherein R _A, R _B , R _C , W, n and R ₃₃ are defined as defined herein.

In some cases, for these embodiments, W is a bond or C1-C3 alkylene or, for example, W is -CH ₂ CH ₂ - and, in particular, W is a direct bond.

When ring A is pyridinyl, it may be, for example, 2-pyridinyl or 3-pyridinyl. In some embodiments, ring A is 2-pyridinyl, that is, the compound of formula (Iu) may be represented by formula (Iv).

Wherein R _A, R _B , R _C , W, n and R ₃₃ are defined as defined herein.

In some cases for these embodiments, the 2-pyridinyl is substituted with only one R ₃₃ moiety. For example, in some embodiments, the 2-pyridinyl is substituted with only one R ₃₃ moiety bonded at position 6 of the pyridinyl ring, and thus this compound can be represented by formula (Iw):

Wherein R _A, R _B , R _C , W, and R ₃₃ are defined as defined herein.

In embodiments wherein ring A is 3-pyridinyl, the compound of formula (Iu) may be represented by formula (Ix):

Wherein R _A, R _B , R _C , W, n and R ₃₃ are defined as defined herein.

In some cases for embodiments wherein ring A is 3-pyridinyl, the 3-pyridinyl is substituted with only one R ₃₃ moiety. For example, in some embodiments, when the 3-pyridinyl is substituted with only one R ₃₃ moiety, the compound of formula (Ix) is represented by formula (Iy)

Wherein R _A, R _B , R _C , W, and R ₃₃ are defined as defined herein.

In compounds of formula (Iu), (Iv), (Iw), (Ix) or (Iy), R ₃₃ is defined as defined herein. In some embodiments, R ₃₃ is halogen, C1-C4 alkyl, _{C3-C6-cycloalkyl, R 34 O (CH 2)} p, R 43 O (CH 2) q C (O), R 38 R 39 N , and R ₄₀ R ₄₁ N (CO).

In some embodiments for compounds of formula (Iu), R _A, R _B, and R _C are independently selected from H, halogen, cyano, and C 1 -C 4 alkyl; W is a direct bond or C1-C3 alkylene; n is 0 or 1; And

R ₃₃ is halogen, R a ₃₄ O, optionally substituted C1-C4 alkyl, C3-C6-cycloalkyl, R ₃₄ O, R ₃₇ C (O), R ₃₈ R ₃₉ N or R ₄₀ R ₄₁ N (CO) Is selected.

In some embodiments of compounds of formula (Io), when ring A is 4- to 6-membered heterocyclyl, ring A is more specifically 4- to 6-membered non-aromatic, , Saturated heterocyclyl. In some embodiments, the heterocyclyl is 4- or 5-membered, for example, 4-membered. In some other embodiments, the heterocyclyl is 5- or 6-membered, for example, 5-membered. In yet another embodiment, the heterocyclyl is 6-membered.

When ring A is a 4- to 6-membered saturated heterocyclyl, the ring preferably contains one or two heteroatoms in the ring, and the heteroatom in each ring is preferably selected from N and O.

In some embodiments, ring A is a 4- to 6-membered saturated saturated heterocyclyl containing one N and one optional O at the ring.

In some embodiments, ring A is a 4- to 6-membered saturated heterocyclyl containing only one ring heteroatom selected from N and O.

In some embodiments, ring A is a 4- to 6-membered saturated heterocyclyl containing only one ring heteroatom, i.

When ring A is a 4- to 6-membered saturated heterocyclyl containing N in the ring, the N may be the point of attachment of the linking moiety W, or, if not, the point of attachment of the N May be substituted with one R ₃₃ moiety or may be non-substituted (i.e., have a hydrogen atom).

In some embodiments, when A is a 4- to 6-membered heterocyclyl containing one N in the ring, the compound of formula (I) may be represented by formula (Iz)

Wherein Z ₁ is (CH ₂ ) _u , Z ₂ is (CH ₂ ) _v , and u and v are both 0 or ₁ , wherein R _1, R _B , R _C and W are defined as defined herein, U + v is an integer from 2 to 4; R ₃₃ 'is H, or R ₃₃ as defined herein above.

In some embodiments of compounds of formula (Iz), u and v are both 1. In some embodiments of compounds of formula (Iz), u + v is 3 or 4. In some cases for these embodiments, u is 0 and v is 3 or 4. In some other instances of this embodiment, u is 1 and v is 2 or 3. In another case of this implementation, u and v are both 2.

In compounds of formula (Iz), R ₃₃ 'is H or R ₃₃ as defined herein above. In some embodiments for compounds of formula (Iz), R ₃₃ 'is C 1 -C 4 alkyl, pyridyl, R ₃₆ S (O) ₂ or R ₃₇ C (O). In some particular embodiments, R ₃₃ 'is R ₃₇ C (O), or R ₃₆ S (O) ₂ ; for example, R ₃₃ ' is R ₃₇ C (O).

In some embodiments for compounds of formula (Io), ring A is a 4- to 6-membered heterocyclyl bonded to a linking moiety W through a ring heteroatom N. For example, in this embodiment, ring A can be morpholin-4-yl, pyrrolidin-1-yl or azetidin-1-yl.

In some embodiments, ring A is morpholin-4-yl. In some embodiments, ring A is pyrrolidin-1-yl.

In some embodiments, when ring A is morpholin-4-yl or pyrrolidin-1-yl, n is 0. In some embodiments, when ring A is morpholin-4-yl or pyrrolidin-1-yl, W is C1-C3 alkylene.

In some embodiments, ring A is azetidin-1-yl. In some embodiments, when ring A is azetidin-1-yl, n is 2, and two R ₃₃ are bonded to the same carbon atom and are F.

In some embodiments, when ring A is azetidin-1-yl, W is C1-C3 alkylene.

In certain embodiments, when ring A is 4- to 6-membered heterocyclyl,

R _A, R _B and R _C are independently selected from H, halogen and C 1 -C 4 alkyl,

W is a direct bond or C1-C3 alkylene;

n is an integer from 0 to 2; And

Each R ₃₃ is independently selected from halogen, C 1 -C 4 alkyl, pyridyl, and R ₃₇ C (O).

More preferably, when ring A is C4-C6 cycloalkyl or C5-C6 cycloalkenyl, it is C4-C6 cycloalkyl. In some embodiments for compounds of formula (Io), ring A is C4 to C6 cycloalkyl, i.e., cyclobutyl, cyclopentyl, or cyclohexyl. In these embodiments, the compound can be represented by formula (Iaa):

Wherein R _A, R _B , R _C , W, R ₃₃ and n are as defined herein and r is an integer from 1 to 3.

In the compounds of formula (Iaa), the moiety W is defined herein as defined above. In some embodiments, the moiety W is a direct bond, a C1-C3 alkylene or a C1-C3 alkylene substituted with a C1-C4 alkyl, for example W is a direct bond or a C1-C3 alkylene, especially W Is a direct bond, CH ₂ , CH ₂ CH ₂ or CH ₂ CH ₂ CH ₂ .

In some embodiments for compounds of formula (Iaa), W is a direct bond. In some other embodiments, W is R ₃₂ O or a C1-C4 alkyl optionally substituted, C1-C3 alkylene; In particular, W is C 1 -C 3 alkylene optionally substituted by C 1 -C 4 alkyl, for example, W is CH ₂ , CH ₂ CH ₂ or CH ₂ CH ₂ CH optionally substituted by C 1 -C 4 alkyl ₂ , in particular W is CH ₂ CH ₂ optionally substituted by C ₁ -C 4 alkyl. In some embodiments, W is CH ₂ , CH ₂ CH _2, or CH ₂ CH ₂ CH ₂ .

In the compounds of formula (Iaa), r is an integer from 1 to 3. In some embodiments, r is 2 or 3, and therefore ring A is cyclopentyl or cyclohexyl, such as cyclohexyl. In some other embodiments, r is 1 or 2, and therefore ring A is cyclobutyl or cyclopentyl. In certain embodiments, r is 2, and therefore ring A is cyclopentyl.

In some particular embodiments for compounds of formula (Iaa), W is CH ₂ CH ₂ , r is 2, and n is an integer defined as defined herein above, preferably n is 0, 1 Or 2, for example, n is 0 or 1. In some embodiments for compounds of formula (Iaa), n is 0. In some embodiments for compounds of formula (Iaa), n is 1, for example n is 1 and R ₃₃ is R ₃₄ O, especially OH.

In some embodiments of the compounds of formula (Iaa), when n is 2, two R ₃₃ are attached to one and the same carbon atom of ring A to form a viro radical -CH ₂ -L-CH ₂ - , Wherein L is CH ₂ , NH or O, for example L is NH.

For example, expression in some embodiments of the compounds of (Iaa), r is 1, and n is 2, the two R ₃₃ present in the compounds may be coupled to one and the same carbon atom by a radical CH ₂ - It forms an L-CH _2. In some cases for these embodiments, the compound of formula (Iaa) may be represented by formula (Iab):

Wherein R _A, R _A, R _B , R _C , R ₃₃ , W, r and L are defined as hereinbefore defined.

In some embodiments for compounds of formula (Iab), r is 1. In some embodiments for compounds of formula (Iab), L is NH. In certain embodiments of compounds of formula (Iab), r is 1 and L is NH.

In some embodiments for compounds of formula (Iaa)

R _A, R _B and R _C are independently H, halogen, cyano, C1-C4 alkyl, R ₁ O, R ₂ C (O), R ₃ S, and R ₄ S (O), or selected from _2, Or one of R _A and R _C together with R _B forms a bi-radical - (CH ₂ ) _m - wherein m is an integer from 3 to 5; And the other of R _A and R _C is selected from H, halogen, cyano, C ₁ -C 4 alkyl, R ₁ O, R ₂ C (O), R ₃ S and R ₄ S (O) ₂ ;

R ₁ , R ₂ , R ₃ and R ₄ are independently selected from C 1 -C 4 alkyl;

W is a direct bond or C1-C3 alkylene optionally substituted by C1-C4 alkyl;

n is an integer from 0 to 2;

R ₃₃ is OH, or when n is 2, two R ₃₃ are bonded to one and the same carbon atom to form a bi-radical -CH ₂ -NH-CH ₂ -.

In the compounds of the present invention, any alkyl may be optionally substituted with one or more F, whether or not part of the functional group.

Through studies, the efficacy of the compounds of this invention has been demonstrated in vitro and in vivo in mice, and although these compounds have been developed to inhibit S100A9, they may also be active against other S100 proteins. Accordingly, the present invention relates to a S100 protein inhibitor, its use as a S100A9 inhibitor, and its use in the treatment or prevention of diseases associated with S100-protein related diseases, particularly the activity of the S100A9 protein.

In particular, the invention relates to the use of a compound of formula (I) as defined herein, a pharmaceutical composition comprising said compound, in particular in the therapeutic treatment of a condition selected from autoimmune diseases, inflammatory diseases and neurodegenerative diseases, The use of these compositions, methods of treatment of such conditions, and in particular the above compounds for use in the treatment of conditions selected from autoimmune diseases, inflammatory diseases and neurodegenerative diseases as well as cancer, as well as pharmaceutical compositions for the treatment of the above- To the use of such compounds in the preparation of the compositions.

The present invention provides a pharmaceutical composition comprising at least one compound according to formula (I) or an individual isomer thereof, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients, Optionally together with other therapeutic and / or prophylactic ingredients.

The pharmaceutical composition according to the present invention may be for local (local) or systemic administration, for example, for enteral or parenteral administration such as rectal or oral administration to a mammal, Or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount as an active ingredient, in combination with a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier. The therapeutically effective amount of the active ingredient is as defined herein before and is, for example, determined by the species, weight, age, individual symptoms, individual pharmacokinetic data of the mammal, the disease to be treated and the mode of administration.

For intestinal administration, such as oral administration, the compounds of the present invention can be formulated in a wide variety of dosage forms. The pharmaceutical compositions and dosage forms may contain the compounds or compounds of the present invention or pharmaceutically acceptable salt (s) thereof as the active ingredient. The pharmaceutically acceptable carrier may be liquid or solid. Solid form preparations include powders, tablets, pills, lozenges, capsules, cachets, suppositories and dispersing granules. Solid carriers may also include one or more substances that may act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials. In the case of powders, the carrier is an undifferentiated solid which is generally a mixture with the undifferentiated active ingredient. In the case of tablets, the active ingredient is usually mixed with a carrier having the appropriate proportion of the requisite binding capacity and squeezed to the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, And the like. Formulations of the active compounds may include encapsulating materials as carriers, which provide encapsulated, with or without a carrier, the active ingredient surrounded by a carrier and in combination with it.

Other forms suitable for oral administration include liquid preparations such as emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions or the like, or solid preparations intended to be converted into preparations in liquid form immediately prior to use. The emulsions may be prepared in solution, for example in aqueous propylene glycol solution, or may contain emulsifying agents such as lecithin, sorbitan monooleate or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding thereto suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions may be prepared by dispersing the undifferentiated active ingredient in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents. Solid form preparations include solutions, suspensions and emulsions, and may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.

Examples of compositions for rectal administration include, but are not limited to, suitable non-irritating excipients such as, for example, cocoa butter, synthetic glyceride esters or polyethylene glycols which are solid at ordinary temperatures but which are liquefied and / &Lt; / RTI &gt;

The compounds of the invention may also be administered parenterally, for example, by inhalation, by injection or infusion, for example, by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, intraventricular, Intrathecal, intracranial, intracranial, intratumoral, intradermal, and subcutaneous injection or infusion.

Thus, for parenteral administration, the pharmaceutical compositions of the present invention may be in the form of a sterile injectable or infusible preparation, for example in the form of a sterile aqueous or oily suspension. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e. G., Tween 80) and suspending agents. The sterile injectable or infusible preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. For example, the pharmaceutical composition may be a solution in 1,3-butanediol. Other examples of acceptable vehicles and solvents that may be employed in the compositions of the present invention include, but are not limited to, mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are also conveniently used as a solvent or suspending medium. For this purpose, any blend of non-volatile oils such as synthetic mono- or diglycerides may be used. Fatty acids such as oleic acid and its glyceride derivatives can be used in the preparation of injectables, such as olive oil or castor oil, especially pharmaceutically acceptable natural oils such as polyoxyethylated versions of their oils. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersing agent.

In addition, solutions for parenteral use may also contain suitable stabilizers and, if necessary, buffer substances. Suitable stabilizers include antioxidants such as sodium bisulfate, sodium sulfite or ascorbic acid, citric acid and its salts and sodium EDTA, which are included alone or in combination. The parenteral solution may also contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.

For inhalation or nasal administration, suitable pharmaceutical formulations are, for example, as particles, aerosols, powders, mist or droplets having an average size of about 10 microns or less in diameter. For example, the composition for inhalation may be a saline solution, such as benzyl alcohol or other suitable preservative, an absorption enhancer to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art, &Lt; / RTI &gt;

In addition, the pharmaceutical composition of the present invention can be administered topically to the skin or mucosa. For topical administration, the pharmaceutical compositions may be, for example, lotions, gels, pastes, tinctures, transdermal patches, and transmucosal gels. The composition may be formulated into a suitable ointment containing the active ingredient suspended or dissolved in the carrier. Carriers for topical administration of the compositions according to the present invention include, but are not limited to, mineral oils, liquid petroleum jelly, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying waxes and water. In another embodiment, the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetyl alcohol, 2-octyldodecanol, benzyl alcohol and water. In addition, the pharmaceutical compositions of the present invention may be topically applied to the lower intestinal tract as a suitable enema formulation or as rectal suppository formulations.

Suitable pharmaceutical excipients, e. G., Carriers and methods of preparation of pharmaceutical dosage forms are described in Remington ' s Pharmaceutical Sciences, a standard reference in the field of drug formulations.

The pharmaceutical compositions may comprise from about 1% to about 95%, preferably from about 20% to about 90% of a compound of formula (I), together with one or more pharmaceutically acceptable excipients. In general, the compounds of the present invention will be administered in therapeutically effective amounts via any accepted mode of administration for a substance that provides similar uses. The appropriate daily dosage will typically be in the range of 1 to 1000 mg, such as 1-500 per day, depending on the age and relative health of the patient, the potency of the compound used, the route and form of administration, mg or 1 to 50 mg per day. One of skill in the art of treating such diseases will be able to ascertain a therapeutically effective amount of a compound of the invention for a given disease based on the skill of the application and the individual knowledge without undue experimentation. The compounds of the present invention may be administered as pharmaceutical preparations such as formulations suitable for enteral or parenteral administration. A preferred mode of administration is oral administration using conventional daily dosage regimens which can generally be adjusted according to the degree of pain.

In one aspect, the present invention provides a method of treating a subject suffering from a condition selected from the group consisting of a member of the S100 protein family, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a warm-blooded animal, For example, a disease responsive to the inhibition of S100A9, for example, cancer, an autoimmune disease, an inflammatory disease, or a neurodegenerative disease.

In some embodiments, the treatment disorder according to the present invention is cancer, for example, a cancer as defined herein above.

In some other embodiments, the therapeutic disorder according to the present invention is an autoimmune disorder, for example, an autoimmune disorder as defined herein above.

In some other embodiments, the therapeutic disorder according to the present invention is an inflammatory disorder, for example, an inflammatory disorder as defined herein above.

In some other embodiments, the therapeutic disorder according to the present invention is a neurodegenerative disorder, for example, a neurodegenerative disorder as defined herein above.

The preparation of the compounds according to the invention will be sufficient within the ability of those skilled in the art. For example, the compounds of formula (I) can be prepared by the reaction sequence generally illustrated in scheme 1. That is, in a general method for preparing a compound of formula (I) as defined herein, the primary amide ( 1 ) is first reacted with an alkyl group, such as alkyl, In the presence of 3-trifluoro-2-oxopropanoate ( 2 ) and an organic base such as pyridine or triethylamine in a suitable solvent medium such as DMF, DMSO or N-methylpyrrolidine the reaction was then added to the reagent of thionyl chloride or oxalyl chloride and the like, to produce the "acyl imine intermediate" in the general formula 3.

Then, by reacting an acyl imine (3) from the amino-benzimidazole (4) and a suitable solvent medium, such as DMF, DMSO or N- methylpyrrolidine, R _A, R _A, R _B, R _C, (I) wherein R &lt; ₃₃ &gt;, n, W and ring A are defined as hereinbefore.

                         Scheme 1

The following examples will enable those skilled in the art to more clearly understand and to practice the present invention. However, these embodiments are not to be construed as limiting the scope of the invention, but are to be regarded primarily as examples and as examples.

Examples

All pyridines used were anhydrous (stored on activated 4 A molecular sieves).

All of the DMF used was anhydrous (active 4 A molecular sieve).

All the nomenclatures for the molecules were performed using MarvinSketch 14.10.27.0.

The HPLC method is as follows:

"Low pH Method A" refers to an HPLC method using a mobile phase consisting of 0.2% formic acid in water with a gradient of 0-100% MeCN. The stationary phase consists of a Waters Sunfire C18 column, 10 mu m particle size, 30 x 100 mm.

"Low pH Method B" refers to an HPLC method using a mobile phase consisting of 0.1% formic acid in water with a 0-100% MeCN concentration gradient. The stationary phase consisted of a Waters Sunfire C18 column, 5 mu m particle size, 19 x 100 mm.

"High pH method" refers to an HPLC method using a mobile phase composed of a 0.2% aqueous ammonia solution with a gradient of 5-100% MeCN in water. The stationary phase consists of a Waters X-bridge C18 column, 10 μm particle size, 30 x 100 mm.

"Neutral" refers to an HPLC method using a mobile phase (no modifier added) consisting of a 10-100% MeCN concentration gradient in water. The stationary phase consists of a Waters Sunfire C18 column, 10 mu m particle size, 30 x 100 mm.

SFC chromatography was performed on a Chiralpak AD-H column with mobile phase of methanol containing supercritical CO ₂ and 0.1% formic acid.

Microwave reactions were performed using CEM Discover, Biotage Initiator + or Activent microwave devices.

The term "acylimine intermediate product" refers to the reaction product between the primary amine (RCONH ₂ ) and alkyl 3,3,3-trifluoro-2-oxopropanoate. General formula:

For example, the reaction products between benzamide and methyl 3,3,3-trifluoro-2-oxopropanoate, namely (methyl (2Z) -2 - {[(Z) -benzoyl] , 3,3-trifluoropropanoate) is considered to be an "acylimine intermediate product ".

Intermediate product 1

(Z) -methyl 2- (benzoylimino) -3,3,3-trifluoropropanoate

To a stirred solution of benzamide (3.00 g, 24.8 mmol) in DMF (60 mL) was added pyridine (2.00 mL, 24.8 mmol) followed by methyl 3,3,3-trifluoro-2-oxopropanoate 3.86 g, 24.8 mmol) was added dropwise under nitrogen, and the solution was stirred for 1 hour. Additional methyl 3,3,3-trifluoro-2-oxopropanoate (1.53 g) was added and the reaction stirred for an additional 2 hours. The resulting solution was cooled to 0 &lt; 0 &gt; C under nitrogen, thionyl chloride (1.80 mL, 24.8 mmol) was added and the solution was stirred for another 2 h at 0 <0> C. The reaction mixture was concentrated. The residue was filtered through a silica short pad using EtOAc as eluent to give the title compound (5.47 g, 85%); MeOH adduct was observed in MS: m / z = 291.8 (MH) ^&lt; ⁺ & gt ^; .

MeOH adduct was observed in MS:

Intermediate 2

N- [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] prop-

To a stirred solution of acrylamide (1.00 g, 14.1 mmol) in anhydrous DMF (25 mL) under nitrogen was added pyridine (1.13 mL, 14.1 mmol) followed by methyl 3,3,3-trifluoro- Oxopropanoate (1.45 mL, 14.1 mmol). The reaction mixture was stirred at room temperature for 1 hour and then thionyl chloride (1.02 mL, 14.1 mmol) was added dropwise. The solution was stirred for 3 hours at room temperature and then concentrated. The residue was filtered through a silica short pad eluting with EtOAc (100 mL) and the filtrate was concentrated. The remaining acylimine intermediate product was dissolved in anhydrous DMF (20 mL) and 2-aminobenzimidazole (1.87 g, 14.1 mmol) and triethylamine (1.87 mL, 14.1 mmol) were added under nitrogen. The solution was stirred and stirred for 16 hours and then concentrated. The residue was dissolved in EtOAc (25 mL) and rinsed with water (25 mL) and brine (25 mL). Dry (MgSO _4), filtered and the organic phase was then concentrated. The crude product was purified by silica chromatography using 0-5% MeOH in DCM as eluent to give the title compound as a white solid (1.05 g, 24%); m / z = 311.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 3

3-Cyclopentylpropanamide

A solution of 3-cyclopentylpropanoyl chloride (5.00 g, 31.1 mmol) in anhydrous THF (40 mL) was added to a solution of ammonia (9.35 mL, 93.4 mmol) and THF (10 mL) Lt; / RTI &gt; The solution was warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated and partitioned between water (50 mL) and EtOAc (3 x 25 mL). Combined organic phases were dried (MgSO _4), filtered and concentrated to afford the 3-cyclopentyl-propanamide as a white solid (3.95 g, 90%); ¹ H NMR (500 MHz, chloroform - d) δ 0.97 - 1.11 ( m, 2H). 1.39-1.50 (m, 2H), 1.50-1.62 (m, 4H), 1.63-1.76 (m, 3H), 2.11-2.20 (m, 2H), 5.47 (s,

Intermediate 4

(Z) -methyl 2 - ((3-cyclopentylpropanoyl) imino) -3,3,3-trifluoropropanoate

(Z) -methyl 2- (benzoylimino) -3,3,3-trifluoropropanoate was used, but 3-cyclopentylpropanamide was used instead of benzamide. No additional addition of methyl 3,3,3-trifluoro-2-oxopropanoate was required. The eluent is 50-100% EtOAc / heptane (66%); The H ₂ O adduct was observed in MS: m / z = 296.1 (M-1) ^- .

Intermediate 5

(Z) -methyl 3,3,3-trifluoro-2 - ((3-phenylpropanoyl) imino) propanoate

(Z) -methyl 2- (benzoylimino) -3,3,3-trifluoropropanoate was used, but 3-phenylpropanamide was used instead of benzamide. There was no need to add additional methyl 3,3,3-trifluoro-2-oxopropanoate; (99%); H ₂ O adduct The product was observed on MS: m / z = 306.1 (MH) ⁺ .

H ₂ O adducts observed in MS:

Intermediate 6

3- (2-chlorophenyl) propanamide

To a solution of 3- (2-chlorophenyl) propanoic acid (1.0 g, 5.42 mmol) in DCM (100 mL) was added thionyl chloride (0.39 mL, 5.42 mmol) dropwise under nitrogen. The solution was stirred at room temperature for 3 hours and then concentrated. The residue was dissolved in anhydrous Dissolved in THF (10 mL), and cooled to 0 占 폚. 7M ammonia / methanol (1.55 mL) was added dropwise under nitrogen. The reaction was stirred at room temperature for 4 hours and then concentrated. The residue was dissolved in EtOAc (50 mL) and rinsed with saturated _{NaHCO 3 (aq) (2 x} 25 mL) and Dublin (25 mL). The organic phase was dried (MgSO ₄ ), filtered and concentrated to give the title compound as a yellow solid (530 mg, 53%); m / z = 183.9, 185.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate product 7

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] prop-

To a stirred solution of acrylamide (1.00 g, 14.1 mmol) in DMF (25 mL) was added methyl 3,3,3-trifluoro-2-oxopropanoate (1.45 mL, 14.1 mmol) under nitrogen Then, pyridine (1.13 mL, 14.1 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0 &lt; 0 &gt; C. Thionyl chloride (1.02 mL, 14.1 mmol) was added dropwise to this solution. The reaction mixture was warmed to room temperature, stirred again between 24 and concentrated. The acylimine intermediate product was dissolved in DMF (25 mL), and triethylamine (1.87 mL, 14.1 mmol) and 5,6-dimethyl-1H-1,3-benzodiazole- mol) were added under nitrogen. The reaction mixture was stirred at room temperature for 5 hours and then concentrated. The residue was dissolved in DCM (100 mL) and then rinsed with water (2 x 100 mL). The organic phase was dried (MgSO _4), filtered and concentrated. The crude product was purified by silica chromatography using 0-5% MeOH in DCM as eluent to give the title compound as a white solid (1.30 g, 27%); m / z = 339.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate product 8

6- (2,2,2-Trifluoroethoxy) pyridine-3-carboxamide

To a stirred solution of 6- (2,2,2-trifluoroethoxy) pyridine-3-carboxylic acid (1.00 g, 4.52 mmol) in DCM (50 mL) and DMF (0.1 mL) was added thionyl chloride 4.52 mmol) was added dropwise under nitrogen. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue was dissolved in anhydrous THF (25 mL) and cooled to 5 &lt; 0 &gt; C, then an excess of aqueous ammonia solution was added. The reaction mixture was warmed to room temperature and stirred for 3 hours. The mixture was extracted with EtOAc (3 x 50 mL) and the combined organic phases were washed with saturated NaHCO ₃ (aq) (50 mL) and brine (50 mL). The organic phase was dried (MgSO ₄ ), filtered and concentrated to give the title compound as a white solid (798 mg, 80%); m / z = 221.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate product 9

5,6-Dichloro-lH-l, 3-benzodiazole-2-amine

The title compound was prepared according to International Application No. PCT / US2007 / 020982 (publication number WO2008042282) (quantitative yield); m / z = 201.8, 203.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate product 10

tert -Butyl 6-carbamoyl-2-azaspiro [3.3] heptane-2-carboxylate

To a solution of 2 - [( tert -butoxy) carbonyl] -2-azaspiro [3.3] heptane-6-carboxylic acid (700 mg, 2.90 mmol) in DCM (100 mL) was added triethylamine 386 [mu] L, 2.90 mmol). The reaction was cooled to 0 C and chloro (ethoxy) methanone (304 L, 3.19 mmol) was added dropwise. The reaction was warmed to room temperature and stirred for 2 hours. The reaction was then cooled to 0 &lt; 0 &gt; C and then aqueous ammonia solution (290 [mu] L, 2.90 mmol) was added. The reaction was warmed to room temperature and stirred for 3 hours. The reaction was diluted with DCM (100 mL) and rinsed with water (3 x 50 mL) and 10% NaHCO ₃ (aq) (50 mL). And the organic phase dried (MgSO _4), filtered and concentrated to give the title compound as a white solid (601 mg, 86%); ^{m / z = 184.9 (MH- t} Bu) +.

Intermediate product 11

tert -Butyl 6 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (12), 6,8,10-tetraen-3-yl] carbamoyl} -2- azaspiro [3.3] heptane-

To a stirred solution of tert -butyl 6-carbamoyl-2-azaspiro [3.3] heptane-2-carboxylate Pyridine (173 l, 2.14 mmol) and methyl 3,3,3-trifluoro-2-oxopropanoate (669 mg, 4.29 mmol) were added under nitrogen to a solution of the title compound (515 mg, 2.14 mmol) The reaction mixture was stirred at room temperature for 16 h and then cooled to 0 &lt; 0 &gt; C. To this was added thionyl chloride (156 mL, 2.14 mmol) dropwise and the solution was stirred at 0 &lt; 0 &gt; C for 1 h and then concentrated. The residue was filtered through a silica schott pad, DCM / DMF (10: 1), and the filtrate was concentrated. The remaining acylimine intermediate product was dissolved in DMF (20 mL) under nitrogen. (325 mg, 1.61 mmol) and triethylamine (285 [mu] L, 2.14 mmol) were added to this solution and the reaction was stirred at room temperature for 3 h Stirred for a time and then concentrated. The residue was dissolved in EtOAc (50 mL) and rinsed with water (3 x 50 mL) and brine (2 x 50 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography, eluting with 0-7% MeOH in DCM to give the title compound as an off-white solid (411 mg, 35%); m / z 491.8, 493.8 (MH-tBu) ^&lt; ⁺ & gt ^; .

Intermediate product 12

3- (2,6-dichlorophenyl) propanamide

To a stirred solution of 3- (2,6-dichlorophenyl) propanoic acid (1.00 g, 4.59 mmol) in DCM (20 mL) was added thionyl chloride (1.67 mL, 23.0 mmol) dropwise under argon. The reaction mixture was refluxed for 3 hours and then concentrated. The residue was dissolved in DCM (10 mL) and cooled to 0 &lt; 0 &gt; C. Ammonia gas was bubbled into the reaction for 10 minutes. The reaction was concentrated and diluted with water (10 mL). The white solid produced was collected via filtration and then dried to give the title compound as a white solid (700 mg, 70%); m / z = 218.3, 220.3 (MH) ^&lt; ⁺ & gt ^; .

Intermediate product 13

6- (cyclohexylamino) pyridine-3-carboxamide

To a solution of 6-chloropyridine-3-carboxamide (1.00 g, 6.40 mmol) in NMP (5 mL) was added N, N -diisopropylethylamine (2.19 mL, 12.8 mmol) and cyclohexyl Amine (2.93 mL, 25.6 mmol). The reaction mixture was heat-treated in a microwave at 200 &lt; 0 &gt; C for 1 hour and then concentrated. The residue was purified by silica chromatography using 2% MeOH in DCM as eluent to give the title compound as an off-white solid (350 mg, 25%); m / z = 220.2 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 14

3- (Pyridin-3-yl) propanamide

Oxalyl chloride (0.84 ml, 9.81 mmol) was added dropwise to a solution of 3- (pyridin-3-yl) propionic acid (500 mg, 3.27 mmol) in DCM (10 mL) at 0 ° C. The reaction was warmed to room temperature, stirred for 3 hours and then concentrated. The residue was dissolved in DCM (15 mL), cooled to 0 &lt; 0 &gt; C, and ammonia gas was bubbled through the solution for 15 min. The reaction was then concentrated and the white solid produced was triturated in water (8 mL). The solid was filtered and dried in vacuo to give the title compound as a white solid (200 mg, 40%); m / z = 151.2 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 15

4- (pyrrolidin-1-yl) butanamide

An aqueous ammonia solution (303 L, 16.2 mmol) was added to a solution of ethyl 4- (pyrrolidin-l-yl) butanoate (1.00 g, 5.40 mmol), prepared according to International Application No. PCT / US2009 / 050797 (publication number WO2010009290) In a sealed tube. The reaction was stirred at room temperature for 16 hours and then concentrated. The residue was purified by silica chromatography using 5% MeOH in DCM as eluent to give the title compound as a colorless oil (750 mg, 89%); ^{1 H NMR (400 MHz, DMSO-} d 6) δ 1.57 - 1.72 (m, 8H), 2.01 - 2.09 (m, 2H), 2.28 - 2.36 (m, 2H), 2.50 - 2.58 (m, 2H), 6.68 (s, 1 H), 7.20 (s, 1 H).

Intermediate product 16

Ethyl 4- (morpholin-4-yl) butanoate

To a stirred solution of ethyl 4-bromobutanoate (2.93 mL, 20.0 mmol) in toluene (30 mL) was added morpholine (7.14 mL, 80.0 mmol). The solution was refluxed for 10 hours. The resulting white solid was filtered and rinsed with diethyl ether (100 mL). Concentration of the filtrate gave the title compound as a yellow oil (3.20 g, 78%); ¹ H NMR (400 MHz, DMSO- d ₆ )? 1.17 (t, 3H), 1.62-1.70 (m, 2H), 2.21-2.32 (m, 8H), 3.51-3.57 , 2H).

Intermediate product 17

4- (morpholin-4-yl) butanamide

An aqueous ammonia solution (4 mL) was added to ethyl 4- (morpholin-4-yl) butanoate (700 mg, 3.30 mol) and the reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated and azeotroped with toluene to give the title compound as a yellow semi-solid (410 mg, 65%); ^{1 H NMR (400 MHz, DMSO-} d 6) δ 1.62 - 1.70 (m, 2H), 2.21 - 2.32 (m, 8H), 3.51 - 3.57 (m, 4H), 7.22 (s, 2H).

Intermediate 18

Amino] -3,3,3-trifluoro-2- [3- (morpholin-4-yl) Yl) propanamido] propanoate

, Literature (You et. Al. In DMF (5 mL), Ethyl 3,3,3-trifluoro-2-oxopropanoate (419 μL, 3.16 mmol) was added to a solution of 3- (morpholin-4-yl) propanamide mmol) and pyridine (269 [mu] L, 3.16 mmol). The reaction mixture was stirred at room temperature for 2 hours under argon, then thionyl chloride (230 L, 3.16 mmol) was added dropwise to this solution. Stirring was continued for a further 24 hours and then the reaction was concentrated. The acylimine produced was dissolved in DMF (5 ml) and then added to a solution of 5,6-dichloro-1H-1,3-benzodiazole-2-amine (615 mg, 3.05 mmol) in DMF . Triethylamine (422 L, 3.05 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction was diluted with brine (25 mL) and extracted with EtOAc (2 x 35 mL). The organic phases were combined, rinsed with water, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica chromatography using 2% MeOH in DCM as eluent to give the title compound as a brown oil (427 mg, 1%); m / z = 512.5 (MH) ^&lt; ⁺ & gt ^; .

Intermediate product 19

tert -Butyl 2- (2-carbamoylethyl) piperidine-1-carboxylate

To the stirred solution of 3- {1 - [( tert -butoxy) carbonyl] piperidin-2-yl} propanoic acid (200 mg, 0.78 mmol) in chloroform (20 mL) mmol) and isobutyl chloroformate (93 [mu] L, 0.78 mmol) were added at 0 [deg.] C under argon. The reaction mixture was stirred at room temperature for 2 hours and then ammonia gas was bubbled through the reaction mixture for 15 minutes. The reaction mixture was diluted with DCM and rinsed with 5% NaHCO3 _(aq) and 1M HCl _(aq) . The organic phase was dried (Na ₂ SO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 2% MeOH in DCM as eluent to give the title compound as a colorless oil (110 mg, 55%); ¹ H NMR (400 MHz, DMSO- d ₆ )? 1.16-1.26 (m, 1H), 1.37 (s, 9H), 1.43-1.64 , 3.80 (d, IH), 4.07 (s, IH), 6.70 (s, IH), 7.24 (s, IH).

Intermediate 20

tert -Butyl 4- (carbamoylmethyl) piperidine-1-carboxylate

tert - butyl-2- (2-carbamoyl-ethyl) piperidine but using the production method of 1-carboxylate, 3- {1 - [(tert - butoxy) carbonyl] piperidin-2-one } 2- {l - [( tert -butoxy) carbonyl] piperidin-4-yl} acetic acid was used instead of propanoic acid (72%); ^{1 H NMR (400 MHz, DMSO-} d 6) δ 0.90 - 1.04 (m, 2H), 1.37 (s, 9H), 1.52 - 1.64 (m, 2H), 1.72 - 1.84 (m, 1H), 1.90 - 2.00 (m, 2H), 2.66 (s, 2H), 3.87 (d, 2H), 6.75

Intermediate product 21

1H, 5H, 6H, 7H-indeno [5,6-d] imidazol-

Dichloro-1H-1, 3-benzodiazole-2-amine was used instead of 4,5-dichlorobenzene-1,2-diamine, but using 2,3- -Indene-5,6-diamine (quantitative yield); m / z = 173.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate products 22

4,5-Dimethyl-1H-1,3-benzodiazole-2-amine

Dichloro-1H-1,3-benzodiazole-2-amine was used but the 3,4-dimethylbenzene-1,2-diamine was converted to 4,5-dichlorobenzene- Instead of 1,2-diamine (83%); m / z = 162.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 23

4-methyl-1H-1,3-benzodiazole-2-amine

Dichloro-1H-1,3-benzodiazole-2-amine was used but 3-methylbenzene-1,2-diamine was converted to 4,5- dichlorobenzene- -Diamine (quantitative yield); m / z = 148.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 24

4,5-Difluoro-lH-l, 3-benzodiazole-2-amine

The procedure for the preparation of 5,6-dichloro-1H-1,3-benzodiazole-2-amine was used but 3,4-difluorobenzene-1,2-diamine was converted to 4,5- -1,2-diamine (60%); m / z = 170.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 25

3,4-dichlorobenzene-l, 2-diamine

To a solution of 2,3-dichloro-6-nitroaniline (1.08 g, 5.21 mmol) in MeOH (4.40 mL), according to the method of Carta et al ., 2007, concentrated HCl (6.60 mL) Was added tin (II) chloride dihydrate (4.71 g, 20.87 mmol). The reaction was heat-treated at 70 ° C for 4 hours. The reaction mixture was concentrated to ½ volume, basified with 5M NaOH (aq), then diluted with EtOAc (20 mL) and stirred for 30 min. The formed precipitate was filtered off. The filtrate was rinsed with brine (20 mL), dried (Na ₂ SO ₄ ), filtered and concentrated to give the desired product as a light brown solid (0.87 g, 94%); m / z = 176.9, 178.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 26

4,5-Dichloro-lH-l, 3-benzodiazole-2-amine

Dichloro-1H-1,3-benzodiazole-2-amine was used but the 3,4-dichlorobenzene-1,2-diamine was converted to 4,5-dichlorobenzene- Instead of 1,2-diamine (48%); m / z = 201.9, 203.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 27

4-Chloro-lH-l, 3-benzodiazole-

Dichloro-lH-l, 3-benzodiazole-2-amine was used but using 3-chlorobenzene-l, 2-diamine (Available according to the method described in International Application No. PCT / US2008 / 003935 (publication number WO2008118454)) was used instead of 4,5-dichlorobenzene-1,2-diamine (57%); m / z = 167.9, 169.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 28

Chloro-lH-imidazo [4,5-c] pyridin-2-amine

To a solution of 2-chloropyridine-3,4-diamine (0.92 g, 6.42 mmol) in DCE (36 mL) was added ethyl N-carboly oil carbamate (0.83 mL, 7.1 mmol) dropwise under nitrogen. After 10 minutes, EDC.HCl (1.35 g, 7.1 mmol) and N, N-diisopropylethylamine (5.60 mL, 32.1 mmol) were added. After refluxing for 2 hours, the reaction was concentrated. The residue was dissolved in 1 M NaOH (aq) (50 mL), rinsed with DCM (2 x 40 mL) and neutralized with 1 M HCI. The resultant precipitate was collected via filtration and then tritylated in DCM. The carbamate was taken up in EtOH (10 times volume) and 2M NaOH (aq) (3 eq) was added. The reaction was heated to reflux for 8 hours. The reaction was concentrated and taken up in water and neutralized with 3M HCl (aq), extracted with propan-2-ol / chloroform (3 x 50 mL), dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound Obtained as a white solid (0.43 g, 40%). m / z = 168.9, 170.9 (MH) &lt; + &gt;.

Intermediate 29

4,6-Difluoro-lH-l, 3-benzodiazole-2-amine

Dichloro-lH-1,3-benzodiazole-2-amine was used but 3,5-difluorobenzene-l, 2-diamine was converted to 4,5-dichlorobenzene -1,2-diamine (48%); m / z = 169.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 30

Oxa-4-carboxamide

Triethylamine (1.28 mL, 9.22 mmol) and isobutyl chloroformate (884 L, 7.37 mmol) were added to a stirred solution of oxalic acid-4-carboxylic acid (800 mg, 6.15 mmol) in chloroform (5 mL) &Lt; / RTI &gt; The reaction mixture was stirred at 0 &lt; 0 &gt; C for 2 hours, then ammonia gas was passed through the solution for 15 minutes. The reaction mixture was concentrated. The residue was dissolved in propan-2-ol / chloroform (1: 4, 25 mL ₎ and rinsed sequentially with water, 5% NaHCO _{3 (aq)} and 1M HCl _(aq) . The organic phase was dried (Na ₂ SO _4), filtered, and concentrated. The crude product was purified by tritylation in DCM to give the title compound as a white solid (1.20 g, 91%); ^{1 H NMR (400 MHz, DMSO-} d 6) δ 1.44 - 1.63 (m, 4H), 2.23 - 2.34 (m, 1H), 3.27 (td, 2H), 3.82 (ddd, 2H), 6.75 (s, 1H ), 7.22 (s, 1 H).

Intermediate 31

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] prop-

To a stirred solution of prop-2-enamide (170 mg, 2.38 mmol) in DMF (8 mL) was added methyl 3,3,3-trifluoro-2-oxopropanoate (400 L, 3.96 mmol) (190 [mu] L, 2.38 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 2 hours. Thionyl chloride (180 [mu] L, 2.38 mmol) was added dropwise at 0 [deg.] C and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was filtered through a silica short pad eluting with DCM and under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (6 mL) under nitrogen. Acyl intermediate solution was added to a solution of 5,6-dichloro-1H-1,3-benzodiazole-2-amine (400 mg, 1.98 mmol) in DMF (8 ml) Mu] l, 2.38 mmol). The reaction mixture was stirred for 17 h and then concentrated. The residue was dissolved in EtOAc (25 mL) and rinsed with water (30 mL). The aqueous phase was extracted with EtOAc (20 mL) and the combined organic extracts were rinsed with 10% citric acid _(aq) (2 x 15 mL) and brine (25 mL), dried (MgSO ₄ ), filtered and concentrated . The crude product was triturated in DCM and purified by silica chromatography using 0-10% MeOH as eluent to give the title compound as a light brown solid (41 mg, 5%); m / z = 378.8, 380.8 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 32

6 - [(2-methoxyethyl) (methyl) amino] pyridine-2-carboxamide

To a solution of 6-fluoropyridine-2-carboxamide (500 mg, 3.57 mmol) in DMF (10 mL) was added (2-methoxyethyl) (methyl) amine (636 mg, 7.14 mmol) and K ₂ CO ₃ 1.23 g, 8.92 mmol). The reaction mixture was stirred at 100 DEG C for 12 hours. (2-methoxyethyl) (methyl) amine (636 mg, 7.14 mmol) was added and the reaction was further heated at 100 &lt; 0 &gt; C for 7 h. The reaction mixture was then concentrated. The residue was diluted with EtOAc (100 mL) and rinsed with water (3 x 50 mL) and brine (3 x 50 mL). The organic phase was dried (MgSO ₄ ), filtered and concentrated to give the title compound as a white solid (580 mg, 78%); m / z 210.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 33

tert- Butyl 3-carbamoyl-3-fluoroazetidine-1-carboxylate

To a solution of 1 - [( tert -butoxy) carbonyl] -3-fluoroazetidine-3-carboxylic acid (available from the literature: Faming Zhuanli Shenqing, 102731362, 17 Oct 2012) in DCM (70 mL) 1.00 g, 4.56 mmol), DMF (200 L, 2.60 mmol) and oxalyl chloride (490 L, 5.70 mmol) were added at 0 <0> C under nitrogen. The prepared solution was stirred at 0 ° C for 2 hours, and then an aqueous ammonia solution (2.28 ml, 22.81 mmol) was added dropwise to this solution. After stirring for an additional 30 minutes at 0 ° C, the reaction was allowed to warm to room temperature. After stirring for 1 hour, the reaction mixture was diluted with water (30 mL). The organic phase was washed with water (3 x 30 mL), dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound as a yellow solid (990 mg, 99%); ^{m / z = 162.9 (MH- t} Bu) +.

Intermediate 34

3-Cyclobutyl propanamide

Triethylamine (1.00 mL, 7.67 mmol) and ethyl chloroformate (731 L, 7.67 mmol) were added to a stirred solution of 3-cyclobutyl propanoic acid (984 mg, 7.67 mmol) in DCM (50 mL) &Lt; / RTI &gt; The reaction mixture was stirred at room temperature for 2 hours. An aqueous ammonia solution (769 [mu] L, 7.67 mmol) was added at 0 [deg.] C and the reaction was allowed to warm to room temperature over 1 hour. The reaction mixture was diluted with DCM (50 mL) and extracted with water (3 x 100 mL) and 10% NaHCO _{3 (aq)} (100 mL). The combined _organics were acidified with 10% citric acid _(aq) (10 mL) and then extracted with DCM (3 x 75 mL). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated to give the title compound as a white solid (548 mg, 56%); m / z = 128.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 35

3- (3,4,5-trimethoxyphenyl) propanamide

To a stirred solution of 3- (3,4,5-trimethoxyphenyl) propanoic acid (1.00 g, 4.16 mmol) in DCM (20 mL) was added DMF (80 L, 1.04 mmol) and oxalyl chloride (719 L, 8.32 mmol) was added dropwise at 0 &lt; 0 &gt; C under argon. The reaction was allowed to warm to room temperature over 3 hours and then concentrated. The residue was dissolved in DCM, cooled to 0 &lt; 0 &gt; C and the solution was saturated with ammonia gas. The reaction mixture was stirred for 2 hours and then concentrated. The residue was diluted with water and the resulting precipitate was collected via filtration to give the title compound as a white solid (690 mg, 66%); 1H NMR (400 MHz, DMSO- d 6) δ 2.35 (t, 2H), 2.74 (t, 2H), 3.62 (s, 3H), 3.75 (s, 6H), 6.53 (s, 2H), 6.78 (s , &Lt; / RTI &gt; 1H), 7.30 (s, 1H).

Intermediate products 36

3-methanesulfonylbenzamide

To a stirred solution of 3-methanesulfonylbenzoic acid (1.50 g, 7.49 mmol) in DCM (7 mL) was added dropwise DMF (144 L, 1.87 mmol) and oxalyl chloride (1.29 ml, 14.98 mmol) Respectively. The reaction was allowed to warm to room temperature over 3 hours and then concentrated. The residue was diluted in THF, cooled to 0 &lt; 0 &gt; C, and the resulting solution was saturated with ammonia gas. The reaction mixture was stirred for 2 hours and then concentrated. The residue was diluted with MeOH / DCM and the precipitate formed was filtered off. Concentration of the filtrate gave the title compound as a white solid (750 mg, 42%); m / z = 200.3 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 37

4-Bromo-lH-l, 3-benzodiazole-2-amine

Dichloro-1H-1,3-benzodiazole-2-amine was used but the 3-bromobenzene-1,2-diamine was converted to 4,5-dichlorobenzene- Was used instead of 2-diamine (62%); m / z = 211.8, 213.8 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 38

2-Amino-5-chloro-1H-1,3-benzodiazole-4-carbonitrile

The procedure for the preparation of 5,6-dichloro-1H-1,3-benzodiazole-2-amine was used but that 2,3-diamino-6-chlorobenzonitrile (available via literature method: PCT International Application 2003051277, 26 Jun 2003) was used instead of 4,5-dichlorobenzene-1,2-diamine (60%); m / z = 192.9, 194.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 39

4-Fluoro-lH-l, 3-benzodiazole-2-amine

The procedure for the preparation of 5,6-dichloro-1H-1,3-benzodiazole-2-amine was used but that of 3-fluorobenzene-1,2-diamine (available via literature method: PCT International Application 2002008224, 31 Jan 2002) was used instead of 4,5-dichlorobenzene-1,2-diamine (43%); m / z = 151.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 40

4,6-Dimethyl-1H-1,3-benzodiazole-2-amine

The procedure for the preparation of 5,6-dichloro-1H-1,3-benzodiazole-2-amine was used but 3,5-dimethylbenzene-l, 2-diamine (available via literature method: PCT international application 2003008413, 30 Jan 2003) was used instead of 4,5-dichlorobenzene-1,2-diamine (quantitative yield); m / z = 162.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate products 41

4-Chloro-5-fluoro-3H-l, 3-benzodiazole-

BrCN (198 mg, 1.87 mmol) in MeCN (2 mL) was added to a solution of 3-chloro-4-fluorobenzene-l, 2- diamine ( Oriental Journal of Chemistry , 2007 , 23 , 571-576) (300 mg, 1.87 mmol) in dichloromethane at 0 &lt; 0 &gt; C. After stirring for 18 h, the reaction mixture was diluted with saturated NaHCO _{3 (aq)} (30 mL). The precipitate was filtered off, and the filtrate was concentrated. The residue was diluted with water (30 mL), sonicated, filtered and rinsed with water to give the title compound as an orange-brown solid (110 mg, 32%); m / z = 185.9, 187.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate products 42

5-Chloro-4-methyl-1H-1,3-benzodiazole-

Dichloro-1H-1, 3-benzodiazole-2-amine, but using 4-chloro-3-methylbenzene-l, 2-diamine : U.S. Patent Application Publication No. 20060111416, May 25, 2006) was used instead of 4,5-dichlorobenzene-1,2-diamine (99%); m / z = 181.9, 183.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate product 43

4-chloro-3-fluorobenzene-l, 2-diamine

To a microwave tube was added 1,3-dichloro-2-fluoro-4-nitrobenzene (2.00 g, 9.52 mmol), phenylmethanamine (4.17 mL, 38.1 mmol) and THF (20 mL). The reaction mixture was heat treated in a microwave at 80 &lt; 0 &gt; C for 3 hours and then concentrated. The residue was dissolved in EtOAc (40 mL) and rinsed sequentially with 0.5 M HCl _(aq) (20 mL) and brine (20 mL). The organic phase was dried (Na ₂ SO _4), filtered, and concentrated.

The residue was dissolved in MeOH (15 mL), the flask was vacuum treated and then flushed with nitrogen (x3). To the stirred solution was added 10% Pd / C (60 mg, 0.06 mmol). The flask was vacuum treated, flushed with nitrogen (x 3), then vacuumed again and flushed with hydrogen (x 3). After stirring for 18 hours, the reaction was filtered through celite, rinsed with EtOH and concentrated to give the crude product as brown solid. The crude product was purified by silica chromatography using 20-60% in heptane as eluent to give the title compound as a reddish brown solid (655 mg, 72%); m / z = 160.9, 162.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 44

5-Chloro-4-fluoro-lH-l, 3-benzodiazole-

Dichloro-1H-1,3-benzodiazole-2-amine was used but the 4-chloro-3-fluorobenzene-1,2-diamine was prepared from 4,5- Benzene-l, 2-diamine (99%); m / z = 185.9, 187.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 45

2-fluoro-3-methoxy-6-nitroaniline

The microwave tube was charged with 2,3-difluoro-1-methoxy-4-nitrobenzene (1.00 g, 5.29 mmol) and 7M ammonia / MeOH (15 mL). The reaction mixture was heated in a microwave at 80 &lt; 0 &gt; C for 40 min and then concentrated. The residue was diluted with EtOAc (30 mL) and rinsed with water (30 mL) and brine (30 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated to give the title product as a yellow solid (0.97 g, 99%); m / z = 186.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate product 46

3-fluoro-4-methoxybenzene-l, 2-diamine

The flask filled with 2-fluoro-3-methoxy-6-nitroaniline (0.97 g, 5.26 mmol) and MeOH (25 mL) was vacuum treated and flushed with nitrogen (x 3). Then 10% Pd / C (112 mg, 0.11 mmol) was added to the stirred solution. The flask was vacuum treated, flushed with nitrogen (x3), vacuumed again and flushed with hydrogen (x3). After stirring for 18 hours, the reaction was filtered through celite, rinsed with MeOH and concentrated to give the title compound as a brown solid. (822 mg, 97%). m / z = 157.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 47

4-Fluoro-5-methoxy-lH-l, 3-benzodiazole-

A solution of BrCN (640 mg, 6.04 mmol) in MeCN (2 mL) was added dropwise to a stirred solution of 3-fluoro-4-methoxybenzene-1,2-diamine (820 mg, 5.25 mmol) Respectively. After stirring for 18 hours, the reaction mixture was concentrated. The residue was diluted with saturated NaHCO _{3 (aq)} (20 mL) and sonicated. The precipitate was collected via filtration and then rinsed with water to give the title compound as a red solid (970 mg, quantitative yield); m / z = 182.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 48

7- (trifluoromethyl) -1H-1,3-benzodiazole-2-amine

A solution of 5M BrCN / MeCN (0.87 mL, 4.35 mmol) was added to a stirred solution of 3- (trifluoromethyl) benzene-1,2-diamine (700 mg, 3.97 mmol) in MeCN / water (5: ) At 0 &lt; 0 &gt; C. After stirring for 14 h, the reaction mixture was diluted with saturated NaHCO _{3 (aq)} (10 mL). The precipitate was collected via filtration and then rinsed with water (20 mL) and diethyl ether (40 mL) to give the title compound as a yellow solid (540 mg, 66%); m / z = 202.1 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 49

4- (Methylsulfanyl) -1H-1,3-benzodiazole-2-amine

Dichloro-1H-1,3-benzodiazole-2-amine was used but 3- (methylsulfanyl) benzene-1,2-diamine (available via literature methods : J. Med. Chem . 2005 , 48 , 8253-8260) was used instead of 4,5-dichlorobenzene-1,2-diamine (99%); m / z = 178.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 50

(4S) -4-benzyl-3- (3-cyclopentylpropanoyl) -1,3-oxazolidin-

2.5M n in anhydrous THF (50 mL) a (4S) -4- benzyl-1,3-oxazolidin-2-one (1.00 g, 5.64 mmol) in a solution of hexane (2.26 mL, 5.65 mmol) while stirring -Butyllithium was added dropwise at -78 &lt; 0 &gt; C under nitrogen. The reaction was stirred at -78 &lt; 0 &gt; C for 1 hour and then 3-cyclopentyl propanoyl chloride (864 [mu] L, 5.64 mmol) was added dropwise. The reaction was warmed to room temperature and stirred for an additional hour. The reaction was quenched with saturated NH ₄ Cl _(aq) (25 mL) at 0 ° C, diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). Rinse the combined organic extracts were Dublin, concentrated dry (MgSO ₄₎ and filtered and. The crude product was purified by silica chromatography using 33% EtOAc in heptane as eluent to give the title compound as a white solid (1.55 g, 90%); m / z = 302.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 51

(4S) -4-benzyl-3- [(2S) -2- (cyclopentylmethyl) propanoyl] -1,3-oxazolidin-

To a stirred solution of (4S) -4-benzyl-3- (3-cyclopentylpropanoyl) -1,3-oxazolidin-2-one (1.50 g, 4.98 mmol), 1 M NaHMDS in THF (7.47 mL, 7.47 mmol) was added dropwise at -78 <0> C under nitrogen. The reaction was stirred at -78 &lt; 0 &gt; C for 30 min and then iodomethane (930 l, 14.93 mmol) was added dropwise. After 3 h at -78 &lt; 0 &gt; C, the reaction was allowed to warm to room temperature. After stirring for an additional 2 hours, the reaction was quenched with saturated NH ₄ Cl _(aq) at 0 ° C. After warming to room temperature, the reaction mixture was extracted with EtOAc (3 x 50 mL). Rinse the combined organic extracts were Dublin (50 mL), it was concentrated and dried (MgSO ₄₎ and filtered and. The crude product was purified by silica chromatography using 0-40% EtOAc in heptane as eluent to give the title compound as a white solid (1.03 g, 65%); m / z = 316.2 (MH) ^&lt; ⁺ & gt ^; .

Intermediate products 52

 (2S) -3-cyclopentyl-2-methylpropanoic acid

To a stirred solution of (4S) -4-benzyl-3- [(2S) -2- (cyclopentylmethyl) propanoyl] -1,3-oxazolidin- 3.17 mmol) was added lithium hydroxide monohydrate (532 mg, 12.68 mmol) followed by hydrogen peroxide (570 L, 19.02 mmol). The reaction mixture was stirred at room temperature for 5 hours and then concentrated to half volume. EtOAc (25 mL) and 1 M HCl _(aq) (25 mL) were added, the organic phase was rinsed with brine and then concentrated. The residue was dissolved in EtOAc (25 ml ₎ and extracted with 1 M NaOH _(aq) . The aqueous phase was acidified to pH 3 with 1 M HCl _(aq ) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated to give the title compound as a colorless oil (395 mg); m / z = 178.0 (M + Na) &lt; ⁺ & gt ^; .

Intermediate 53

(2S) -3-cyclopentyl-2-methylpropanamide

To a stirred solution of (2S) -3-cyclopentyl-2-methylpropanoic acid (395 mg, 2.53 mmol), DMF (100 L, 1.30 mmol) and oxalyl chloride (271 L, 3.16 mmol) were added at 0 C under nitrogen. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 3 hours and then an aqueous ammonia solution (1.27 ml, 12.64 mmol) was added. The reaction was warmed to room temperature and stirred for another 2 hours. The reaction mixture was diluted with DCM (50 mL) and rinsed with water (2 x 50 mL) and 10% citric acid _(aq) (2 x 50 mL). The combined aqueous phases were extracted again with DCM (50 mL) and the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated to give the title compound as off-white solid (294 mg, 75%); m / z = 156.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 54

(2S) -1-methanesulfonylpyrrolidine-2-carboxamide

To a solution of (2S) -1-methanesulfonylpyrrolidine-2-carboxylic acid (1.00 g, 5.18 mmol) in DCM (75 mL) was added ethyl chloroformate (510 L, 5.18 mmol) and triethylamine 5.18 mmol) at 0 &lt; 0 &gt; C under nitrogen. The reaction mixture was stirred at room temperature for 3 hours. An aqueous ammonia solution (1.55 mL, 15.53 mmol) was added at 0 &lt; 0 &gt; C. The reaction mixture was stirred for 1 h, then diluted with DCM (25 mL) and extracted with water (3 x 50 mL). The combined organic extracts were concentrated. The residue was diluted with DCM (50 mL), sonicated and filtered. Filtered and dried to a water (MgSO _4), filtered and concentrated to give the title compound as a beige solid (415 mg, 38%); m / z = 192.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 55

Diastereomeric mixture. (S) - {[10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [ ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] carbamoyl} (phenyl)

To: (Org Biomol Chem 2011, 9 , 3011-3019 possible obtainable with the method of the literature...) (0.63 g, 3.26 mmol) solution, - DMF (20 mL) of (S) carbamoyl (phenyl) methyl acetate Methyl 3,3,3-trifluoro-2-oxopropanoate (1.22 g, 7.82 mmol) was added followed by pyridine (315 l, 3.91 mmol) under nitrogen. The solution was stirred for 2 hours at room temperature. Thionyl chloride (284 L, 3.91 mmol) was added dropwise at 0 &lt; 0 &gt; C and the reaction mixture was stirred at 0 &lt; 0 &gt; C for an additional 1 h. The reaction mixture was concentrated and the residue was filtered through a silica short pad eluting with DCM under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (5 mL) under nitrogen. Acyl intermediate was added to a stirred solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (525 mg, 3.26 mmol) in DMF (20 mL) Amine (546 [mu] L, 3.91 mmol). The reaction mixture was stirred for 16 hours and then concentrated. The residue was dissolved in EtOAc (50 mL), which was rinsed with water (4 x 50 mL) and Dublin (3 x 50 mL), dried (MgSO _4), filtered, and concentrated. The crude product was purified by reverse phase C18 chromatography using an acidic eluent to give the title compound as an off-white solid (536 mg, 36%) as a mixture of diastereomers; m / z = 461.0 (MH) ^&lt; ⁺ & gt ^;

Intermediate 56

3-Cyclopentyl- N - [4-oxo-3- (trifluoromethyl) -9- {2- [tris (propan-2-yl) silyl] ethynyl} -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (239986)

A microwave tube N - [9- bromo-4-oxo-3- (trifluoromethyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca-1 (12) , 6,8,10- tetraen-3-yl] -3-cyclopentyl-propanamide (100 mg, 0.22 mmol), copper (I) iodide (2.5 mg, 0.01 mmol), Pd (PPh 3) 2 _{Cl 2 (9.2 mg, 0.01 mmol} ), PPh 3 (11 mg, 0.04 mmol), degassed DMF (1 mL), tris ethynyl (propane-2-yl) silane (121 ㎕, 0.54 mmol) and diethylamine (346 [mu] L, 3.27 mmol). The reaction was stirred in a microwave at 120 &lt; 0 &gt; C for 35 min. The reaction was concentrated. The residue was dissolved in DCM (15 mL), rinsed with water (10 mL) and brine (10 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica chromatography using 0-2% MeOH in DCM as eluent to give the title compound as a brown oil (100 mg, 49%); m / z = 561.2 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 57

4- (trifluoromethoxy) -1H-1,3-benzodiazole-2-amine (239991)

Dichloro-1H-1,3-benzodiazole-2-amine was used but 3- (trifluoromethoxy) benzene-1,2-diamine was prepared from 4,5- dichloro Benzene-l, 2-diamine (91%); m / z = 218.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 58

4-iodo-1H-1,3-benzodiazole-2-amine (239995)

To a stirred solution of 4-bromo-1H-1,3-benzodiazole-2-amine (1.00 g, 4.72 mmol) in dioxane (25 mL) was added potassium iodide (1.57 g, 9.43 mmol) , Copper (I) iodide (90 mg, 0.47 mmol) and N , N' -dimethylethane-l, 2-diamine (102 l, 0.94 mmol). First, the reaction was heated at 100 &lt; 0 &gt; C for 2 hours. The reaction was then heated at 125 &lt; 0 &gt; C for a further 38 h. During this period additional copper iodide (2.35 g, 14.15 mmol), copper (I) iodide (180 mg, 0.94 mmol) and N , N'- dimethylethane- , 1.88 mmol) was added in portions. The reaction was then concentrated and the residue was diluted with EtOAc (40 mL) and water (40 mL). The precipitate formed was filtered off and the aqueous phase extracted with IPA / CHCl ₃ (1: 1, 2 x 40 mL). Rinse the combined organic extracts with a one Dublin (25 mL), dried (MgSO _4), filtered and then concentrated. The crude product was purified by tritylation in DCM to give the title compound as a purple solid (775 mg, 64%); m / z = 259.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 59

Phenyl 3- (3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxylate (239996)

To a sealed tube was added 3-cyclopentyl- N- [9-iodo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] (200 mg, 0.40 mmol), anhydrous MeCN (2 mL), palladium (II) acetate (9 mg, 0.04 mmol) and tri tert -butylphosphonium tetrafluoroborate (46 mg, 0.16 mmol). The reaction was degassed and phenylformate (108 [mu] L, 0.99 mmol) was added followed by triethylamine (137 [mu] L, 0.99 mmol). The reaction product was flushed with nitrogen, sealed, and stirred at 80 DEG C for 16 hours. The reaction was cooled to room temperature and concentrated. The residue was dissolved in EtOAc (8 mL) and rinsed with saturated citric acid _(aq) (2 x 7 mL), water (7 mL) and brine (7 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 0-2% MeOH in DCM as eluent to give the title compound as a yellow solid (65 mg, 64%); m / z = 501.2 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 60

4-Bromo-6-chloro-lH-l, 3-benzodiazol-2-amine (239916)

The procedure for the preparation of 5,6-dichloro-1H-1,3-benzodiazole-2-amine was used but starting from 3-bromo-5-chlorobenzene- Possible: PCT International Application 2013067260) was used instead of 4,5-dichlorobenzene-1,2-diamine (84%); m / z = 245.8, 247.8 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 61

6-Bromo-4-fluoro-lH-l, 3-benzodiazole-2-amine (239926)

5-dichloro-1H-1,3-benzodiazole-2-amine was used but the 5-bromo-3-fluorobenzene- Instead of chlorobenzene-1,2-diamine (quantitative yield); m / z = 229.8, 231.8 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 62

6-Chloro-5-methoxy-lH-l, 3-benzodiazol-2-amine (239941)

Dichloro-1H-1,3-benzodiazole-2-amine was used but the 4-chloro-5-methoxybenzene-l, 2-diamine was prepared from 4,5- Benzene-l, 2-diamine (61%); m / z = 198.0, 199.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 63

2-Bromo-3-methoxy-6-nitroaniline (239933)

To a stirred solution of 2-bromo-3-fluoro-6-nitroaniline (1.00 g, 4.26 mmol) in MeOH (43 mL) under nitrogen was added 5.4 M NaOMe / MeOH (1.7 mL, 9.4 mmol) . The reaction was heated at 90 &lt; 0 &gt; C for 1 h and then concentrated. The residue was diluted with water. The precipitate formed was collected by filtration and rinsed with water to give the title compound as a yellow solid (1.05 g, quantitative yield); m / z = 246.9, 248.8 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 64

3-Bromo-4-methoxybenzene-l, 2-diamine (239933)

A suspension of 2-bromo-3-methoxy-6-nitroaniline (1.15 g, 4.66 mmol) and tin (II) chloride dihydrate (5.25 g, 23.28 mmol) in EtOAc (47 mL) Lt; 0 &gt; C. The reaction was cooled to room temperature and the pH was adjusted to pH 14 using 5 M NaOH _(aq) . The resulting suspension was stirred for 15 minutes, then filtered through Celite (TM) and rinsed with EtOAc. Rinse the organic phase with water, filtered, Dublin, dried (MgSO _4), filtered and concentrated, to give the title compound as a yellow solid (970 mg, 96%); m / z = 216.9, 218.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 65

4-Bromo-5-methoxy-lH-l, 3-benzodiazole-2- amine (239933)

Dichloro-1H-1,3-benzodiazole-2-amine was used but the 3-bromo-4-methoxybenzene- Instead of chlorobenzene-1,2-diamine (58%); m / z = 241.9, 243.9 (MH) ^&lt; ⁺ & gt ^; .

Intermediate products 66

5-Bromo-4-fluoro-lH-l, 3-benzodiazole-2-amine (239937)

Dichloro-1H-1,3-benzodiazole-2-amine was used but the 4-bromo-3-fluorobenzene- Instead of chlorobenzene-1,2-diamine (73%); m / z = 229.8, 231.8 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 67

Ethyl (2S) -2 - [(3-methylbut-2-en-1-yl) oxy] propanoate (239949/239952)

To a suspension of sodium hydride (60%, 0.61 g, 15.24 mmol) in THF (20 mL) at 0 ° C under nitrogen was added a solution of ethyl (2S) -2-hydroxypropanoate g, 12.7 mmol). The reaction was stirred at 0 &lt; 0 &gt; C for 30 min. A solution of 4-bromo-2-methyl-2-butene (2.27 g, 15.2 mmol) in THF (5 mL) was then added dropwise and the reaction mixture was allowed to warm to room temperature. After 18 h, the reaction was diluted with water (20 mL) and EtOAc (20 mL). The phases were extracted with EtOAc (2 x 20 mL). The combined organic extracts were rinsed with brine (20 mL), dried (MgSO ₄ ), filtered and concentrated to give the title compound as a brown oil (2.00 g, 81%); ¹ H NMR (500 MHz, chloroform - d) δ 1.24 (t, 3H), 1.35 (d, 3H), 1.63 (s, 3H), 1.70 (s, 3H), 3.88 (dd, 1H), 3.93 (q , 4.06 (dd, 1H), 4.12-4.20 (m, 2H), 5.28-5.35 (m, 1H).

Intermediate 68

(2S) -2 - [(3-methylbut-2-en-1-yl) oxy] propanoic acid (239949/239952)

To a solution of ethyl (2S) -2 - [(3-methylbut-2- en-1-yl) oxy] propanoate (600 mg, 2.90 mmol) in MeOH (10 mL) ₂ O (609 mg, 14.50 mmol) in water (5 mL). The reaction was stirred at room temperature for 18 hours. The reaction was diluted with EtOAc (20 mL) and extracted with water (20 mL). The aqueous phase was acidified to pH 1 with 3M HCl _(aq ) and extracted with EtOAc (4 x 20 mL). The combined organic extracts were rinsed with brine (30 mL), dried (MgSO ₄ ), filtered and concentrated to give the title compound as a yellow liquid (440 mg, 86%); ¹ H NMR (250 MHz, chloroform - d) δ 1.43 (d, 3H), 1.66 (s, 3H), 1.74 (s, 3H), 3.95 - 4.17 (m, 3H), 5.34 (ddt, 1H), 11.09 (s, 1 H).

Intermediate 69

(2S) -2 - [(3-methylbut-2-en-1-yl) oxy] propanamide (239949/239952)

To a stirred solution of (2S) -2 - [(3-methylbut-2- en-1-yl) oxy] propanoic acid (400 mg, 2.28 mmol) in DCM (5 mL) was added oxalyl chloride 4.51 mmol) was added dropwise. DMF (2 drops) was added and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was dissolved in DCM (5 mL). The prepared solution was added dropwise to an aqueous ammonia solution (1.30 mL, 11.4 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 18 hours and then concentrated. The residue was dissolved in EtOAc (20 mL) and rinsed with water (20 mL). The phases were extracted with EtOAc (3 x 20 mL). The combined organic extracts were rinsed with brine (30 mL), dried (MgSO ₄ ), filtered and concentrated to give the title compound as a yellow solid (200 mg, 54%); ¹ H NMR (250 MHz, chloroform - d) δ 1.40 (d, 3H), 1.68 (s, 3H), 1.76 (s, 3H), 3.86 (q, 1H), 4.04 (d, 2H), 5.27 - 5.40 (m, 1 H), 5.60 (s, 1 H), 6.54 (s, 1 H).

Intermediate 70

(2S) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2 - [(3- methylbut-2- en- 1- yl) oxy] propanamide (239949/239952)

To a solution of amide (2S) -2 - [(3-methylbut-2- en-1-yl) oxy] propanamide (180 mg, 1.145 mmol) in anhydrous DCM (5 mL) ) And methyl 3,3,3-trifluoro-2-oxopropanoate (358 mg, 2.29 mmol) were successively added under nitrogen. The reaction was stirred at room temperature for 1.5 hours. Thionyl chloride (84 [mu] L, 1.2 mmol) was added at 0 [deg.] C. The reaction was stirred at 0 &lt; 0 &gt; C for 1 hour. The reaction mixture was filtered through a silica short pad eluting with DCM under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (3 mL) under nitrogen. A solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (154 mg, 3.57 mmol) in DMF (2 mL) was added followed by the addition of triethylamine (160 μL, 1.15 mmol) Respectively. The reaction was stirred for 2 days and then concentrated. The residue was dissolved in EtOAc and rinsed with brine. The phases were extracted with EtOAc (3 x 25 mL). Dry the combined organic extracts (MgSO _4), filtered, and concentrated. The crude product was dissolved in DCM. The formed precipitate was filtered off. The filtrate was concentrated and the title compound was obtained as an orange solid (270 mg, 67%); m / z = 425.1 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 71

Ethyl (2R) -2 - [(3-methylbut-2-en-1-yl) oxy] propanoate (239958/239959)

Ethyl (2S) -2-hydroxypropanoate was synthesized from ethyl (2S) -2 - [(3-methylbut-2-en-1-yl) oxy] propanoate, ) -2-hydroxypropanoate (84%); ¹ H NMR (500 MHz, chloroform - d) δ 1.25 (t, 3H), 1.36 (d, 3H), 1.63 (s, 3H), 1.69 - 1.72 (m, 3H), 3.90 (dd, 1H), 3.95 (q, 1H), 4.04-4.09 (m, 1H), 4.12-4.23 (m, 2H), 5.30-5.35 (m, 1H).

Intermediate 72

(2R) -2 - [(3-methylbut-2-en-1-yl) oxy] propanoic acid (239958/239959)

(2S) -2 - [(3-methylbut-2-en-1-yl) oxy] propanoic acid, Yl) oxy] propanoate was used instead of ethyl (2S) -2 - [(3-methylbut-2-en-1-yl) oxy] propanoate (91%); ¹ H NMR (250 MHz, chloroform - d) δ 1.45 (d, 3H), 1.68 (s, 3H), 1.76 (s, 3H), 3.97 - 4.18 (m, 3H), 5.30 - 5.40 (m, 1H) , 8.36 (s, 1 H).

Intermediate 73

(2R) -2 - [(3-methylbut-2-en-1-yl) oxy] propanamide (239958/239959)

(2S) -2 - [(3-methylbut-2-en-1-yl) oxy] propanamide was used, -Yl) oxy] propanoic acid was used in place of ethyl (2S) -2 - [(3-methylbut-2-en-1-yl) oxy] propanoic acid (29%); ¹ H NMR (250 MHz, chloroform - d) δ 1.34 (d, 3H), 1.62 (s, 3H), 1.70 (s, 3H), 3.80 (q, 1H), 3.98 (d, 2H), 5.16 - 5.38 (m, 1 H), 6.44 (s, 1 H), 6.56 (s, 1 H).

Intermediate 74

(2R) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2 - [(3-methylbut-2- en- 1- yl) oxy] propanamide (239958/239959)

(2S) - N - [10,11- ( trifluoromethyl) dimethyl-4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca-1 ( 2-en-1-yl) oxy] propanamide but using (2R) -2 2 - [(3-methylbut-2-en-1-yl) oxy] propanamide was used instead of (2S) 68%); m / z = 425.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 75

(2R) -2- (3-chlorophenoxy) propanamide (239968/29969)

Methanesulfonyl chloride (434 μL, 5.61 mmol) was added to a stirred solution of (2S) -2-hydroxypropanamide (500 mg, 5.61 mmol) in anhydrous DCM (50 mL) at 0 ° C. under nitrogen , Triethylamine (783 [mu] L, 5.61 mmol). The reaction was warmed to room temperature and stirred for 1 hour. The reaction was diluted with water, drying the organic phase (MgSO _4), filtered, and concentrated. The residue was dissolved in anhydrous acetonitrile (50 mL) and 3-chlorophenol (721 mg, 5.61 mmol) and K ₂ CO ₃ (776 mg, 5.61 mmol) were added. The resulting suspension was heated at 70 &lt; 0 &gt; C for 16 h and then concentrated. The residue was dissolved in EtOAc (100 mL), rinse with water (100 mL) and Dublin (100 mL) and then dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 0-100% EtOAc in heptane as eluent to give the title compound as a white solid (220 mg, 20%); m / z = 200.2, 202.3 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 76

(2S) -2-cyclohexylpropanamide (239985)

DMF (2 drops) was added to a stirred solution of [( tert -butoxycarbonyl) amino] (cyclohexyl) acetic acid (500 mg, 3.2 mmol) in DCM (50 mL) Thionyl chloride (0.25 mL, 3.4 mmol) was added. The prepared solution was stirred at room temperature for 1.5 hours and then concentrated. The residue was dissolved in anhydrous THF (20 mL). The reaction was cooled to 0 C and 0.5M ammonia in THF (32 mL) was added. The reaction was warmed to room temperature and stirred for 2.5 days. The reaction was concentrated. The residue was dissolved in DCM (30 mL) and rinsed with water (30 mL). The aqueous phase was extracted with DCM (30 mL) and IPA / CHCl ₃ (1: 1, 30 mL). The combined organic extracts were rinsed with brine (30 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was triturated in EtOAc to give the title compound as a white solid (150 mg, 31%); m / z = 156.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 77

Ethyl (2S) -2- (cyclopent-1-en-1-ylmethoxy) propanoate (239997/239998)

To a suspension of sodium hydride (60%, 0.81 g, 20.3 mmol) in THF (35 mL) at 0 ° C under nitrogen was added a solution of ethyl (2S) -2-hydroxypropanoate g, 16.9 mmol). The mixture was stirred at 0 &lt; 0 &gt; C for 30 min. 1- (bromomethyl) cyclopent-1-ene in THF (5 mL) (available obtainable with the method of the literature:... J. Am Chem Soc , 2013, 135, 10769-10775) (3.27 g, 20.3 mmol) was added dropwise at 0 &lt; 0 &gt; C to the reaction mixture. Then, the reaction was warmed to room temperature and stirred for 18 hours. To the reaction mixture was added water (20 mL) and EtOAc (150 mL). The phases were extracted with EtOAc (2 x 20 mL). The combined organic extracts were rinsed with brine (20 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica chromatography using 5-30% EtOAc in heptane as eluent to give the title compound as a yellow material (1.75 g, 50%); ¹ H NMR (500 MHz, chloroform - d) δ 1.31 (t, 3H), 1.42 (d, 3H), 1.86 - 1.98 (m, 2H), 2.29 - 2.39 (m, 4H), 3.97 - 4.04 (m, 2H), 4.16-4.20 (m, 1H), 4.20-4.66 (m, 2H), 5.64-5.70 (m, 1H).

Intermediate 78

(2S) -2- (Cyclopent-1-en-1-ylmethoxy) propanoic acid (239997/239998)

MeOH (12 mL) and water (4 mL) of ethyl (2S) -2- (cyclopent-1-en-1-ylmethoxy) propanoyl the benzoate (1.75 g, 8.39 mmol) solution, 7.5M NaOH _{(aq )} (1.34 mL, 10.1 mmol) was added dropwise. The reaction was stirred at room temperature for 3 hours. MeOH was evaporated and the pH of the residue was adjusted to pH 1 using 1M HCl _(aq) . The acidic aqueous solution was extracted with EtOAc (4 x 20 mL). The combined organic extracts were rinsed with brine (10 mL), dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound as a yellow oil (1.09 g, 76%); ¹ H NMR (500 MHz, chloroform - d) δ 1.48 (d, 3H), 1.89 - 2.00 (m, 2H), 2.28 - 2.42 (m, 4H), 4.07 (q, 1H), 4.11 (d, 1H) , 4.21 (d, 1 H), 5.66-5.74 (m, 1 H).

Intermediate 79

(2S) -2- (cyclopent-1-en-1-ylmethoxy) propanamide (239997/239998)

To a stirred solution of (2S) -2- (cyclopent-1-en-1-ylmethoxy) propanoic acid (1.10 g, 6.46 mmol) in DCM (15 mL) was added oxalyl chloride (832 L, 9.69 mmol) Lt; / RTI &gt; DMF (2 drops) was added and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was dissolved in DCM (15 mL) and aqueous ammonia solution (3 mL) was added. The reaction was stirred at room temperature for 30 minutes and then concentrated. The residue was dissolved in DCM (50 mL) and then washed with water. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound as a brown solid (1.15 g, quantitative yield); ¹ H NMR (500 MHz, chloroform - d) δ 1.43 (d, 3H), 1.94 (m, 2H), 2.24 - 2.43 (m, 4H), 3.91 (q, 1H), 4.04 - 4.19 (m, 2H) , 5.41 (s, 1 H), 5.69 (s, 1 H), 6.57 (s, 1 H).

Intermediate 80

Phenyl 11-chloro-3- (3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxylate (240015)

Phenyl 3- (3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] ), 6,8,10-tetraene-9-carboxylate, but using N - [11-chloro-9-iodo-4-oxo-3- (trifluoromethyl) 5,7-triaza-tricyclo [6.4.0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] -3-cyclopentyl-a propanamide 3-cyclopentyl- N - [9-Iodo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-3-yl] propanamide. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (39%); m / z = 535.2, 537.2 (MH) ^&lt; ⁺ & gt ^; .

Intermediate products 81

2- (2-methoxyethoxy) pyridine-4-carbonitrile (240032)

To a suspension of sodium hydroxide (60%, 347 mg, 8.66 mmol) in dry dioxane (10 mL) was added at 0 C 2-methoxyethan-1-ol (549 mg, 7.22 mmol ) Solution was added dropwise. The reaction was warmed to room temperature and stirred for 2 hours. A solution of 2-chloropyridine-4-carbonitrile (1.00 g, 7.22 mmol) in dry dioxane (5 mL) was added dropwise to the reaction mixture at 0 ° C and then stirred at room temperature for 20 hours. The reaction was diluted with water (40 mL) and EtOAc (40 mL). The phases were extracted with EtOAc (3 x 50 mL). The combined organic extracts were rinsed with brine (30 mL), dried (MgSO ₄ ), filtered and concentrated. To the crude product was added EtOAc (10 mL). The formed precipitate was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica chromatography using 0-100% EtOAc in heptane as eluent to give the title compound as a green oil (255 mg, 20%); m / z = 179.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 82

2- (2-methoxyethoxy) pyridine-4-carboxamide (240032)

Water / EtOH: A stirred during 2 (1 1, 4 mL) (2-methoxyethoxy) pyridine-4-carbonitrile in the solution casting reel _{2M NaOH (aq) (0.65 mL} , 1.3 mmol) and 28% H ₂ O _{2 (aq)} (0.14 mL, 1.3 mmol). The reaction was stirred at room temperature for 18 h and then diluted with saturated NaHCO _{3 (aq)} (20 mL) and EtOAc (20 mL). The phases were extracted with EtOAc (3 x 20 mL). The combined organic extracts were rinsed with brine (30 mL), dried (MgSO ₄ ), filtered and concentrated to give the title compound as a yellow solid (180 mg, 73%); m / z = 197.0 (MH) ^&lt; ⁺ & gt ^; .

Intermediate 83

Phenyl 3- (3-cyclopentylpropanamido) -10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxylate (240026)

To a sealed tube was added 3-cyclopentyl- N- [9-iodo-10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (65%, 300 mg, 0.36 mmol), anhydrous MeCN (8 mg, 0.04 mmol) and tri- tert -butylphosphonium tetrafluoroborate (42 mg, 0.15 mmol). The reaction was degassed and after addition of phenyl formate (0.1 mL, 0.9 mmol), triethylamine (157 L, 0.91 mmol) was added. The reaction product was flushed with nitrogen, sealed, and then stirred at 80 DEG C for 16 hours. Tert -butylphosphonium tetrafluoroborate (42 mg, 0.15 mmol), phenyl formate (0.1 mL, 0.9 mmol), and triethylamine (157 mg, Mu] L, 0.91 mmol). The reaction was flushed with nitrogen, sealed and then stirred for another 6 hours at 80 &lt; 0 &gt; C. The reaction was cooled to room temperature and concentrated. The residue was dissolved in EtOAc (15 mL) and rinsed with saturated citric acid _(aq) (15 mL). The phases were extracted with EtOAc (15 mL). The combined organic extracts were rinsed with water (15 mL) and brine (25 mL), dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by reverse phase C18 chromatography using an acidic eluent to give the title compound as a white solid (115 mg, 58%); m / z = 531.2 (MH) ^&lt; ⁺ & gt ^; .

Example 1

6-chloro -N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] - dodeca-1 (8), 6,9,11-tetraen-3-yl] pyridine-2- carboxamide (ABR 239471)

To a stirred solution of 6-chloropyridine-2-carboxamide (1.00 g, 13.0 mmol) in DMF (8 mL) was added pyridine (1.05 mL, 13.0 mmol) and ethyl 3,3,3-trifluoro- -Propanoate (1.73 mL, 13.0 mmol) was added dropwise under argon. The reaction mixture was stirred at room temperature for 1 hour and then thionyl chloride (0.95 mL, 13.0 mmol) was added dropwise. The reaction mixture was stirred at room temperature for a further 16 h and then concentrated to give the acylimine intermediate product. The acylimine intermediate was dissolved in DMF (5 mL) and a solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (2.03 g, 13.0 mmol) in DMF (7 mL) Then triethylamine (1.80 mL, 13.0 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction was diluted with brine (25 mL) and extracted with EtOAc (2 x 50 mL). Rinse by combining the organic phase with water, then dried (Na ₂ SO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 3% MeOH in DCM as eluent to afford the title compound as an off-white solid (0.6 g, 22%); m / z = 423.4, 425.4 (MH) ^&lt; ⁺ & gt ^;

Example 2

N - [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -6-fluoropyridine-2- carboxamide (ABR 239472)

To a solution of 6-fluoropyridine-2-carboxamide (700 mg, 4.75 mmol) in DMF (7 mL) under argon was added ethyl 3,3,3-trifluoro-2-oxopropanoate , 4.75 mmol) and pyridine (383 [mu] L, 4.75 mmol). The reaction mixture was stirred at room temperature for 1 hour and then thionyl chloride (344 L, 4.75 mmol) was added dropwise. Stirring was continued for another 2.5 hours and then the reaction was concentrated to give the acylimine intermediate product. The obtained acylimine intermediate product was dissolved in DMF (5 mL) and then a solution of 5,6-dichloro-1H-1,3-benzodiazole-2-amine (519 mg, 2.57 mmol) in DMF Was added. Triethylamine (0.35 ml, 2.56 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted with brine (30 mL) and extracted with EtOAc (2 x 50 mL). Rinse by combining the organic phase with water, then dried (Na ₂ SO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 3% MeOH in DCM as eluent to give the title compound as an off-white solid (300 mg, 25%); m / z = 448.4, 450.4 (MH) ^&lt; ⁺ & gt ^; .

Example 3

N- [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] benzamide (ABR 238128)

To a stirred solution of benzamide (1.00 g, 8.26 mmol) in DMF (40 mL) was added pyridine (666 L, 8.26 mmol) followed by methyl 3,3,3-trifluoro-2-oxopropanoate 1.29 g, 8.26 mmol) was added dropwise under nitrogen. The prepared solution was stirred under nitrogen for 30 minutes, then thionyl chloride (0.60 mL, 8.26 mmol) was added and the solution was stirred for another 1 hour at room temperature. Amine (1.10 g, 8.26 mmol) and triethylamine (0.10 mL, 0.72 mmol) were added to the reaction mixture, the solution was stirred at room temperature for 6 hours, And the mixture was stirred for 3 hours. The reaction mixture was concentrated, dissolved in EtOAc (100 mL) and rinsed with water (3 x 50 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography eluting with 20-50% EtOAc in heptane followed by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (12 mg, 0.4%)

Example 4

2-Cyclohexyl- N- [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] acetamide (ABR 238883)

To a stirred solution of 2-cyclohexylacetamide (425 mg, 3.01 mmol) in DMF (15 mL) was added pyridine (243 l, 3.01 mmol) and methyl 3,3,3- 470 mg, 3.01 mmol) under nitrogen. The prepared solution was stirred at room temperature for 1 hour and then thionyl chloride (218 L, 3.01 mmol) was added dropwise under nitrogen at 0 &lt; 0 &gt; C to this solution. The reaction mixture was warmed to room temperature and stirred for another 16 hours. The reaction mixture was concentrated to give the acylimine intermediate product, which was used without further purification.

1H-1,3-benzodiazole-2-amine (95 mg, 0.72 mmol) was added to a portion of the acylimine intermediate product (200 mg, 0.72 mmol) in DMF (5 mL) and then triethylamine , 0.72 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3 hours and then concentrated. The resulting brown oil was purified by automated reverse phase HPLC (low pH method A) to give the title compound as an off-white solid (58 mg, 22%).

Example 5

3- (Morpholin-4-yl) - N- [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 238798)

To a stirred solution of 3- (morpholin-4-yl) propanamide (1.00 g, 6.32 mmol) in DMF (10 mL) was added pyridine (510 L, 6.32 mmol) and methyl 3,3,3- -Oxo-propanoate (649 [mu] L, 6.32 mmol) was added sequentially under nitrogen. The reaction mixture was stirred for 1 hour at room temperature and then thionyl chloride (459 L, 6.32 mmol) was added. The reaction mixture was stirred for 48 h and then concentrated. The residue was dissolved in DCM (10 mL) and filtered through a celite short pad. The filtrate was concentrated to give the acylimine intermediate product (1.2 g) which was used without further purification. 2-Aminobenzimidazole (112 mg, 0.84 mmol) and triethylamine (109 [mu] L, 0.84 mmol) were added to a solution of the acylimine intermediate (250 mg, 0.84 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was purified by silica chromatography using 0-5% MeOH in DCM as eluent to give the title compound as an off-white solid (98 mg, 30%).

Example 6

N- [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (pyrrolidin- 1- yl) propanamide (ABR 238799)

To a solution of 3- (pyrrolidin-1-yl) propanamide (prepared according to literature procedure (You et al ., 2008)) (1.00 g, 7.03 mmol) in DMF (10 mL) Mu] l, 7.03 mmol) was added followed by methyl 3,3,3-trifluoro-2-oxopropanoate (722 [mu] L, 7.03 mmol) under nitrogen. The resulting reaction mixture was stirred at room temperature for 1 hour and then thionyl chloride (510 L, 7.03 mmol) was added. The reaction mixture was stirred at room temperature for a further 6 hours and then concentrated to give the acylimine intermediate product (1.78 g) which was used without further purification. Aminobenzimidazole (95 mg, 0.71 mmol) was added to a solution of the acylimine intermediate (200 mg, 0.71 mmol) in DMF (3 mL) and triethylamine (92 L, 0.71 mmol) . The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in EtOAc (25 mL) and rinsed with water (2 x 20 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 0-5% MeOH in DCM as eluent to give the title compound as an off-white solid (49 mg, 18%).

Example 7

3- (oxan-4-yl) - N- [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 238816)

EtOH (5 mL) and water (trifluoromethyl) the N- [4- oxo-3-stirred during (1.5 mL) mixture -2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] - To a solution of 4-iodooxane (80 mg, 0.26 mmol) and dodeca-1 (8), 6,9,11-tetraen- , Zinc dust (101.0 mg, 1.54 mmol) and copper iodide (98.2 mg, 0.51 mmol) were added under nitrogen. The reaction mixture was sonicated at room temperature for 5 hours. The reaction mixture was filtered through celite and rinsed with EtOAc (3 x 25 mL). Filtration, rinse with water to Dublin (50 mL), dried (MgSO ₄₎ and filtered, and then concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (17 mg, 16%).

Example 8

2-Bromo-N- [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] benzamide (ABR 238803)

To a stirred solution of 2-bromobenzamide (177 mg, 0.88 mmol) in DMF (6 mL) was added pyridine (71 L, 0.88 mmol) and ethyl 3,3,3-trifluoro-2-oxopropanoate (90 [mu] L, 0.88 mol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and then thionyl chloride (64 L, 0.88 mmol) was added dropwise. The reaction mixture was stirred for 16 hours and then concentrated to give the acylimine intermediate product. The acylimine intermediate product was dissolved in DMF (4 mL), and a solution of 1H-1,3-benzodiazole-2-amine (118 mg, 0.88 mmol) in DMF (2 mL) 118 [mu] L, 0.88 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction was rinsed with brine (25 mL) and extracted with EtOAc (2 x 50 mL). Rinse by combining the organic phase with water, then dried (Na ₂ SO _4), filtered, and concentrated. The crude product was purified by preparative TLC in 10% MeOH in DCM to give the title compound as a brown solid (10 mg, 3%).

Example 9

3-Cyclopentyl -N- [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] propanamide (ABR 238789)

2-bromo-N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-4-yl] benzamide was used, but 3-cyclopentylpropanamide was used instead of 2-bromobenzamide. The crude product was purified by silica chromatography using 2.5% MeOH in DCM as eluent (12%).

Example 10

3,5-dimethoxy -N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-4-yl] benzamide (ABR 238802)

2-bromo-N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-4-yl] benzamide was used, but 3,5-dimethoxybenzamide was used in place of 2-bromobenzamide. The crude product was purified (2%) by preparative TLC using 5% MeOH in DCM as eluent.

Example 11

6-methyl -N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-4-yl] pyridine-3- carboxamide (ABR 238843)

2-bromo-N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-4-yl] benzamide was used, but 6-methylpyridine-3-carboxamide was used in place of 2-bromobenzamide. The crude product was purified (2%) by preparative TLC using 10% MeOH in DCM as eluent.

Example 12

3,5-dichloro -N- [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] benzamide (ABR 238895)

2-bromo-N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-4-yl] benzamide was used, but 3,5-dichlorobenzamide was used in place of 2-bromobenzamide. The crude product was purified (8%) by preparative TLC using 5% MeOH in DCM as eluent.

Example 13

3-cyclohexyl -N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-4-yl] propanamide (ABR 238219)

2-bromo-N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-4-yl] benzamide, the following modification was added. In the first reaction step, 3-cyclohexylpropanamide was used instead of 2-bromobenzamide in order to prepare the acylimine intermediate product. After the addition of thionyl chloride, the reaction mixture was stirred for 2 hours instead of 16 hours. In the second reaction step, 1H-1,3-benzodiazole-2-amine was used instead of 1H-1,3-benzodiazole-2-amine and the reaction was stirred for 16 hours instead of 4 hours. The crude product was purified (10%) by preparative TLC using 10% MeOH in DCM as eluent.

Example 14

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] benzamide (ABR 238786)

To a stirred solution of methyl (Z) -benzoylimino-3,3,3-trifluoropropanoate (150 mg, 0.58 mmol) and 5,6-dimethyl-lH-1,3- Amine (93 mg, 0.58 mmol) in tetrahydrofuran (20 mL), triethylamine (60 L, 0.58 mmol) was added under nitrogen. The reaction mixture was stirred at room temperature for 1 hour and then concentrated. The residue was dissolved in EtOAc (25 mL) and rinsed with water (2 x 20 mL) and brine (20 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (47 mg, 21%).

Example 15

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3-phenylpropanamide (ABR 238787)

(500 mg, 3.35 mmol) was dissolved in DMF (15 mL), and methyl 3,3,3-trifluoro-2-oxopropanoate (523.03 mg, 3.35 mmol) and pyridine Mu] L, 3.35 mmol) was added at room temperature under nitrogen. The reaction mixture was stirred for 1 hour and then thionyl chloride (243 [mu] L, 3.35 mmol) was added. The reaction mixture was further stirred at room temperature for 16 hours and then concentrated. The residue was filtered through a silica short plug eluting with EtOAc and the filtrate was concentrated to give the acylimine intermediate product (502 mg) which was used without further purification. Triethylamine (67.17 L, 0.52 mmol) was added to a solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (84.18 mg, 0.52 mmol) in DMF (5 mL) The acylimine intermediate (150 mg, 0.52 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue was dissolved in EtOAc (20 mL) and rinsed with 10% citric acid (aq) (20 mL), water (20 mL) and brine (20 mL). The organic phase was dried (MgSO ₄ ), concentrated and purified by automated reverse phase HPLC (low pH method A) to give the title compound as an off-white solid (76 mg, 35%).

Example 16

3- (2-Chlorophenyl) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] propanamide (ABR 238908)

To a solution of 3- (2-chlorophenyl) propanamide (500 mg, 2.72 mmol) in DMF (10 mL) under nitrogen was added methyl 3,3,3-trifluoro-2-oxopropanoate mg, 2.72 mmol) followed by pyridine (220 [mu] L, 2.72 mmol). The reaction mixture was stirred at room temperature for 2 hours and then thionyl chloride (198 [mu] L, 2.72 mmol) was added. The reaction mixture was stirred for an additional 16 hours and then concentrated. The residue was filtered through a celite pad and eluted with EtOAc, then filtered through silica and the filtrate was concentrated to give the acylimine intermediate product as a yellow oil (850 mg) which was used without further purification Respectively. A portion of the acylimine intermediate (100 mg, 0.31 mmol) was added to a solution of 5,6-dimethyl-1H-1,3-benzodiazol-2-amine (50 mg, 0.31 mmol) in DMF (5 mL) Triethylamine (41 [mu] L, 0.31 mmol) was then added under nitrogen. The reaction mixture was further stirred at room temperature for 8 hours. The reaction mixture was concentrated and purified by automated reverse phase HPLC (low pH method A) to give the title compound as a beige solid (30 mg, 21%).

Example 17

3,5-Dichloro- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] benzamide (ABR 239340)

To a stirred solution of 3,5-dichlorobenzamide (300 mg, 1.58 mmol) in DMF (20 mL) was added pyridine (127 L, 1.58 mmol) followed by methyl 3,3,3-trifluoro- -Oxo-propanoate (370 mg, 2.37 mmol) was added under nitrogen. The reaction mixture was stirred at room temperature for 2 hours and then cooled to 0 &lt; 0 &gt; C. Thionyl chloride (115 [mu] L, 1.58 mmol) was added dropwise and the solution was stirred at this temperature for an additional 1 h. The reaction mixture was concentrated and passed through a silica short pad, eluting with EtOAc under nitrogen. The filtrate was evaporated immediately and the remaining acylimine intermediate product was redissolved in DMF (10 mL). To this solution was added 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (191 mg, 1.18 mmol) and triethylamine (210 μL, 1.58 mmol). The resulting reaction mixture was stirred for 3 hours and then concentrated. The residue was dissolved in EtOAc (40 mL) and rinsed with water (2 x 30 mL) and brine (2 x 30 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (high pH method) to give the desired product as a white solid (45 mg, 6%).

Example 18

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -4-phenylbenzamide (ABR 239078)

Methyl 3,3,3-trifluoro-2-oxopropanoate (198 mg, 1.27 mmol) was added to a stirred solution of 4-phenylbenzamide (250 mg, 1.27 mmol) in DMF (15 mL) , Pyridine (102 [mu] L, 1.27 mmol) was added under nitrogen. The reaction mixture was stirred at room temperature for 16 hours and then cooled to 0 &lt; 0 &gt; C. Thionyl chloride (92 L, 1.27 mmol) was added dropwise and the reaction was allowed to warm to room temperature. The reaction was stirred for an additional 2 h and then concentrated. The residue was filtered through a silica shorting pad eluting with EtOAc and the filtrate was concentrated to give the acylimine intermediate product. The acylimine intermediate product was dissolved in DMF (10 mL), and then 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (204 mg, 1.27 mmol) Mu] l, 1.27 mmol). The reaction mixture was stirred at room temperature and then at 80 &lt; 0 &gt; C for 18 hours. The reaction mixture was then concentrated. The crude product was purified by silica gel chromatography eluting with 0-5% MeOH in DCM followed by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (38 mg, 6%).

Example 19

4-Cyclopentyl- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] butanamide (ABR 238854)

To an oven dried flask was added N- [10,11-dimethyl-3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Enamide (80 mg, 0.24 mmol), followed by the addition of EtOH (5 mL) and (iodomethyl) cyclopentane (99 mg, 0.47 mmol). Zinc dust (93 mg, 1.42 mmol) and copper iodide (90 mg, 0.47 mmol) were added to the reaction mixture followed by water (1.5 mL). The reaction mixture was degassed with nitrogen for 2 minutes and the suspension was placed in an ultrasonic bath at room temperature for 6 hours. To the reaction mixture was added additional copper iodide (90 mg, 0.47 mmol), zinc dust (93 mg, 1.42 mmol) and (iodomethyl) cyclopentane (99 mg, 0.47 mmol) And ultrasonicated. The reaction mixture was filtered through a pad of celite and further rinsed with EtOAc (100 mL). The organic filtrate was concentrated and purified by silica chromatography using 5-10% MeOH in DCM as eluent as an eluent and then purified by automated reverse phase HPLC (low pH method A) to give the title compound as a beige solid (11 mg, 11%).

Example 20

2-Cyclohexyl- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] acetamide (ABR 238884)

To an oven dried flask was added 2-cyclohexylacetamide (425 mg, 3.01 mmol) followed by DMF (15 mL) and pyridine (243 L, 3.01 mmol) under nitrogen. Methyl 3,3,3-trifluoro-2-oxopropanoate (470 mg, 3.01 mmol) was added to this solution and stirred for 1 hour. Thionyl chloride (218.4 [mu] L, 3.01 mmol) was added dropwise to this solution at 0 [deg.] C under nitrogen. The reaction mixture was warmed to room temperature and stirred for an additional 16 hours. The reaction mixture was concentrated to give the acylimine intermediate product, which was used without further purification. (200 mg, 0.72 mmol) was dissolved in DMF (5 mL), and 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (115 mg, Ethylamine (95 L, 0.72 mmol) was added under nitrogen. The reaction mixture was stirred at room temperature for 3 hours. The reaction was concentrated under high vacuum and then purified by automated reverse phase HPLC (low pH method A) to give the title compound as an off-white solid (150 mg, 51%).

Example 21

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 (8), 6,9,11-tetraen-3-yl] -6- (2,2,2-trifluoroethoxy) pyridine-3- carboxamide (ABR 238950)

Pyridine (183 쨉 L, 2.27 mmol) was added to a solution of 6- (2,2,2-trifluoroethoxy) pyridine-3-carboxamide (500 mg, 2.27 mmol) in DMF (15 mL) Methyl 3,3,3-trifluoro-2-oxopropanoate (354 mg, 2.27 mmol) was added under nitrogen. The solution was stirred at room temperature for 1 hour and then cooled to 0 &lt; 0 &gt; C. Thionyl chloride (165 [mu] L, 2.27 mmol) was added dropwise and the reaction mixture was stirred at room temperature for a further 16 h and then concentrated. The acylimine intermediate product (643 mg, 1.8 mmol) and 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (289.38 mg, 1.8 mmol) were dissolved in DMF And triethylamine (0.24 mL, 1.8 mmol) was added under nitrogen. The reaction mixture was stirred at room temperature for 16 hours and then concentrated. The resulting residue was trytrated in DCM / MeOH (20: 1). The off-white solid produced was collected by filtration. 50 mg of the solid product sample was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (25 mg, 3%).

Example 22

1-cyclopentanecarbonyl- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] pyrrolidine-3- carboxamide (ABR 239208)

In anhydrous DCM (3 mL), a N- [(trifluoromethyl) 10,11-dimethyl-4-oxo-3-stirred during -2,5,7- triaza-tricyclo - [6.4.0.0 ^2,6 }] Dodeca-1 (12), 6,8,10-tetraen-3-yl] pyrrolidine-3- carboxamide hydrochloride (95 mg, 0.23 mmol) , Cyclopentanecarbonyl chloride (29 [mu] L, 0.24 mmol) was added followed by triethylamine (63 [mu] L, 0.45 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours. Water (10 mL) and DCM (10 mL) were added to the vigorously stirred reaction mixture for 5 min. After layer separation, the aqueous layer was extracted again with DCM (2 x 20 mL). The combined organic phases were dried (MgSO ₄ ), filtered and concentrated to give the crude product (containing a mixture of four stereoisomers) as a brown oil. This was separated by SFC using a Chiralpak AD-H column and mobile phase with CO ₂ containing 0.1% formic acid and MeOH to give the title compound isomer (6 mg, 6%) which had no stereochemical properties.

Example 23

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (morpholin-4- yl) propanamide (ABR 238814)

Pyridine (510 L, 6.32 mmol) was added to a stirred solution of 3- (morpholin-4-yl) propanamide (1.00 g, 6.32 mmol) in DMF (10 mL) Fluoro-2-oxo-propanoate (649 [mu] L, 6.32 mmol) was added under nitrogen. The reaction mixture was stirred for 1 hour at room temperature and then thionyl chloride (459 L, 6.32 mmol) was added. The reaction mixture was stirred for an additional 48 h and then concentrated. The residue was dissolved in DCM (10 mL) and filtered through a celite short pad. The filtrate was concentrated to give the acylimine intermediate product (1.2 g) which was used without further purification. Amine (136 mg, 0.84 mmol) in DMF (3 ml) was added dropwise to a stirred solution of the intermediate (250 mg, 0.84 mmol) After addition, triethylamine (109 [mu] L, 0.84 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue was dissolved in DCM (25 mL) and rinsed with water (2 x 25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a pale yellow solid (36 mg, 10%).

Example 24

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] pyrrolidine-3- carboxamide hydrochloride (ABR 239077)

To a stirred solution of tert -butyl 3 - {[10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza- tricyclo [ .0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] carbamoyl} pyrrolidin-1-carboxylate (110 mg, 0.23 mmol) in 2M HCl solution / Ether (114 [mu] L, 0.23 mmol) was added dropwise under nitrogen. The reaction mixture was stirred at room temperature for 16 hours and then concentrated to give the title compound as a white solid as a mixture of stereoisomers (94 mg, 98%).

Example 25

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] piperidine-4- carboxamide hydrochloride (ABR 239205)

To a stirred solution of tert -butyl 4 - {[10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-tri azatricyclo [6.4.0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] carbamoyl} piperidine-1-carboxylate (715 mg, 1.44 mmol ) Was added 2M HCl / ether (1.44 mL, 2.88 mmol) dropwise under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. The reaction was concentrated, azeotroped with diethyl ether (2 x 20 mL) and then vacuum dried to give the title compound as a hydrochloride salt as a beige solid (609 mg, 98%).

Example 26

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -1- (2-methoxyacetyl) piperidine- 4- carboxamide (ABR 239227)

A N- [(trifluoromethyl) 10,11-dimethyl-4-oxo-3-stirred during DCM (10 mL) -2,5,7- triaza-tricyclo - [6.4.0.0 ^2,6] (75 mg, 0.17 mmol) in dichloromethane (10 ml) was added 2-methoxyacetyl chloride (23 mg, 0.21 mmol) and triethylamine (46 [mu] L, 0.35 mmol) were sequentially added at 0 [deg.] C under nitrogen. The reaction mixture was warmed to room temperature and stirred for 4 hours. The mixture was diluted with DCM (30 mL) and rinsed with water (2 x 20 mL). The organic phase was concentrated and purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (17 mg, 21%).

Example 27

3-Cyclopentyl -N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 238788)

Tricyclo [6.4.0.0 &lt; ^2,6 &gt;] dodeca-1 (12), 6, Tetraen-4-yl] benzamide, but using 5,6-dimethyl-1H-1,3-benzodiazole-2-amine with 1H-1,3-benzodiazole -2-amin e, 3-cyclopentylpropanamide was used instead of 2-bromobenzamide (10%).

Example 28

6-chloro -N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] - dodeca-1 (12), 6,8,10-tetraen-3-yl] pyridine- 3- carboxamide (ABR 238911)

Tricyclo [6.4.0.0 &lt; ^2,6 &gt;] dodeca-1 (12), 6, Tetraen-4-yl] benzamide, but using 5,6-dimethyl-1H-1,3-benzodiazole-2-amine with 1H-1,3-benzodiazole -2-amin e, 6-chloropyridine-3-carboxamide was used in place of 2-bromobenzamide. The crude product was purified by silica chromatography using 3% MeOH in DCM as eluent (13%).

Example 29

3- (2,6-dichlorophenyl) -N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] propanamide (ABR 238998)

Tricyclo [6.4.0.0 &lt; ^2,6 &gt;] dodeca-1 (12), 6, Tetraen-4-yl] benzamide, but using 5,6-dimethyl-1H-1,3-benzodiazole-2-amine with 1H-1,3-benzodiazole -2-amine, 3- (2,6-dichlorophenyl) propanamide was used instead of 2-bromobenzamide. The crude product was purified by silica chromatography using 3% MeOH in DCM as eluent (3%).

Example 30

2-bromo -N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] benzamide (ABR 239004)

Tricyclo [6.4.0.0 &lt; ^2,6 &gt;] dodeca-1 (12), 6, Tetraen-4-yl] benzamide, but using 5,6-dimethyl-1H-1,3-benzodiazole-2-amine with 1H-1,3-benzodiazole Amine. &Lt; / RTI &gt; The crude product was purified by silica chromatography using 3% MeOH in DCM as eluent (3%).

Example 31

6- (cyclohexylamino) -N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] pyridine-3- carboxamide (ABR 239024)

Tricyclo [6.4.0.0 &lt; ^2,6 &gt;] dodeca-1 (12), 6, Tetraen-4-yl] benzamide, but using 5,6-dimethyl-1H-1,3-benzodiazole-2-amine with 1H-1,3-benzodiazole -2-amin e, 6- (cyclohexylamino) pyridine-3-carboxamide was used in place of 2-bromobenzamide. The crude product was purified by silica chromatography using 3% MeOH in DCM as eluent (6%).

Example 32

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -6- methylpyridine- 3- carboxamide (ABR 239031)

Tricyclo [6.4.0.0 &lt; ^2,6 &gt;] dodeca-1 (12), 6, Tetraen-4-yl] benzamide, but using 5,6-dimethyl-1H-1,3-benzodiazole-2-amine with 1H-1,3-benzodiazole -2-amin e, 6-methylpyridine-3-carboxamide was used in place of 2-bromobenzamide. The crude product was purified by silica chromatography using 3% MeOH in DCM as eluent (6%).

Example 33

3-cyclohexyl -N- [10,11-Dimethyl-3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-4-yl] propanamide (ABR 238804)

2-bromo-N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-4-yl] benzamide was used, but the following modifications were applied. In the first reaction step, 3-cyclohexylpropanamide was used instead of 2-bromobenzamide in order to prepare the acylimine intermediate product, and after the addition of thionyl chloride, the reaction mixture was stirred for 2 hours instead of 16 hours. In the second reaction step, 5,6-dimethyl-1H-1,3-benzodiazol-2-amine was used in place of 1H-1,3-benzodiazole- Lt; / RTI &gt; The crude product was purified (3%) by preparative TLC using 10% MeOH in DCM as eluent.

Example 34

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (pyridin- 3- yl) propanamide (ABR 239084)

2-bromo-N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-4-yl] benzamide was used, but the following modifications were applied. In the first reaction step, 3- (pyridin-3-yl) propanamide was used in place of 2-bromobenzamide for the preparation of the acylimine intermediate product and the reaction mixture was diluted with 2 Lt; / RTI &gt; In the second reaction step, 5,6-dimethyl-1H-1,3-benzodiazol-2-amine was used in place of 1H-1,3-benzodiazole- Stir for 16 hours. The crude product was purified by silica chromatography using 4% MeOH in DCM as eluent (1%).

Example 35

6- (cyclohexylamino) -N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] pyridine-2- carboxamide (ABR 238974)

To a solution of 6-chloro- N- [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7- triaza- tricyclo [6.4.0.0 ^{2, 6} ] dodeca-1 (8), 6,9,11-tetraen-3-yl] pyridine-2- carboxamide (200 mg, 0.47 mmol) in N, N -diisopropylethylamine 0.16 mL, 1.89 mmol) and cyclohexylamine (0.22 mL, 1.89 mmol) were added sequentially. The reaction mixture was heated in a microwave at 200 &lt; 0 &gt; C for 1 hour and then concentrated. The residue was purified by silica chromatography using 5% MeOH in DCM as eluent to give the title compound as a yellow solid (15 mg, 7%).

Example 36

6-cyclohexyl -N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] - dodeca-1 (12), 6,8,10-tetraen-3-yl] pyridine- 2- carboxamide (ABR 239059)

Microwave tube 6-Chloro -N- [10,11- dimethyl-4-oxo-3- (trifluoro-methyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] 2-carboxamide (100 mg, 0.24 mmol), cyclohexeneboronic acid (29 mg, 0.24 mmol), SPhos (9 mg, 0.02 mmol), Na ₂ CO ₃ (50 mg, 0.47 mmol) and DMF / water (9: 1, 10 mL). The reaction mixture was degassed with argon for 15 minutes. Palladium (II) acetate (5 mg, 0.02 mmol) was added and the reaction mixture was heated in a microwave at 100 &lt; 0 &gt; C for 30 min. The reaction was cooled to room temperature and filtered through a celite pad. The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude compound was purified by automated reverse phase HPLC (low pH method B) to give the title compound as an off-white solid (10 mg, 9%).

Example 37

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3-phenylpropanamide (ABR 239019)

To a stirred solution of methyl (2E) -3,3,3-trifluoro-2 - [(3-phenylpropanoyl) imino] -propanoate (100 mg, 0.35 mmol) in DMF (5 mL) (46 μL, 0.35 mmol) was added to a solution of 6-dichloro-1H-1,3-benzodiazole-2-amine (70 mg, 0.35 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 16 hours and then concentrated. The residue was purified by silica chromatography using 0-10% MeOH in DCM as eluent to give the title compound as an off-white solid (57 mg, 36%).

Example 38

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] benzamide (ABR 238949)

To a stirred solution of 5,6-dichloro-1H-1,3-benzodiazol-2-amine (100 mg, 0.49 mmol) and methyl (Z) -benzoylimino-3,3,3 -Trifluoropropanoate (128 mg, 0.49 mmol) in dichloromethane (5 mL) was added triethylamine (66 L, 0.49 mmol) under nitrogen. The reaction mixture was stirred and concentrated at room temperature for 16 h and purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (24 mg, 11%).

Example 39

3-Cyclopentyl- N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 238926)

To a stirred solution of 3-cyclopentylpropanamide (3.50 g, 24.8 mmol) in DMF (50 mL) was added methyl 3,3,3-trifluoro-2-oxopropanoate (3.87 g, 24.8 mmol) Then pyridine (2.00 mL, 24.8 mmol) was added at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 4 hours and then cooled to 0 &lt; 0 &gt; C. Thionyl chloride (1.80 mL, 24.8 mmol) was added dropwise to this solution, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and eluted with DCM (100 mL) through a silica short pad and filtered. The filtrate was concentrated and the remaining acylimine intermediate product was immediately dissolved in DMF (30 mL) under nitrogen. 5,6-Dichloro-lH-l, 3-benzodiazole-2-amine (4.01 g, 19.8 mmol) was added to the solution followed by triethylamine (3.96 mL, 29.7 mmol). The resulting mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in EtOAc (200 mL), which was rinsed with water (4 x 100 mL) and Dublin (2 x 100 mL), then dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography eluting with 3% MeOH in DCM as eluent to give a dark brown foam. This was dissolved in MeOH (100 mL) and decolorized with charcoal. The resulting suspension was filtered through celite and rinsed with MeOH. The filtrate was concentrated and the title compound was obtained as a pale yellow solid (3.2 g, 29%).

Example 40

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-azaspiro [3.3] heptane- 6- carboxamide (ABR 239424)

To a stirred solution of tert -butyl 6 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7 triazatricyclo [6.4.0.0 ^{2, 3} ] yl] carbamoyl} -2-azaspiro [3.3] -heptane-2-carboxylate (100 mg, 0.18 mmol) in tetrahydrofuran Was added dropwise TFA (1.0 mL, 13.1 mmol). The solution was stirred at room temperature under nitrogen for 16 hours and then concentrated. The resulting solid was azeotroped with diethyl ether and dried in vacuo to give the title compound as a pale pink solid (78 mg, 76%) as a TFA salt.

Example 41

Diastereomeric mixture. (2S) - N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] pyrrolidine-2- carboxamide (ABR 239426)

tert - butyl - (2S) -2 - {[ 10,11- -dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triaza-tricyclo - [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] carbamoyl} pyrrolidine- 1 -carboxylate (50 mg, 0.1 mmol) was dissolved in DCM , TFA (0.5 mL, 3.3 mmol). The reaction mixture was stirred at room temperature for 16 hours and then concentrated. The resulting solid was azeotroped with toluene (2 x 20 mL) and dried in vacuo to give the title compound as a mixture of diastereomers as a TFA salt (49 mg, 95%).

Example 42

Diastereomer mixture N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] pyrrolidine-3- carboxamide (ABR 239136)

To a stirred solution of tert -butyl 3 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4. 0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] carbamoyl} pyrrolidin-1-carboxamide in the carboxylate (466 mg, 0.89 mmol) solution of 2M HCl / Ether (0.67 mL, 1.34 mmol) was added dropwise under nitrogen. The reaction mixture was stirred for 24 hours and then concentrated. Then 100 mg of sample was purified by automated reverse phase HPLC (high pH method) to give the title compound as a mixture of diastereomers (34 mg) as a white solid of hydrochloride salt.

Example 43

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] piperidine-4- carboxamide (ABR 239206)

tert -butyl-4 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] 1-carboxylate (810 mg, 1.51 mmol) was dissolved in diethyl ether (20 mL) and DCM (20 mL, ). 2M HCl / ether (6.04 mL, 12.08 mmol) was added portionwise over 74 h. The reaction mixture was concentrated and the resulting solid was triturated with ether. A sample of this material was purified by automated reverse phase HPLC (high pH method) to give the title compound as a white solid (7 mg).

Example 44

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 (12), 6,8,10-tetraen-3-yl] -1- (2-methoxyacetyl) piperidine- 4- carboxamide (ABR 239228)

DCM (10 mL) a N- [(trifluoromethyl) 10,11-dichloro-4-oxo-3-stirred during -2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] Pyridine-4-carboxamide hydrochloride (75 mg, 0.16 mmol) in dichloromethane (10 ml) under nitrogen was added triethylamine (42 Mu] l, 0.32 mmol) followed by the addition of 2-methoxyacetyl chloride (21 mg, 0.19 mmol). The reaction mixture was stirred at room temperature for 2 hours, then diluted with DCM (20 mL) and rinsed with water (2 x 20 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 5-10% MeOH in DCM as eluent to give the title compound as a yellow solid in about 75% purity (16 mg, 20%). The title compound was tested by biological analysis without further purification.

Example 45

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -1- (3-methylbutanoyl) piperidine- 4- carboxamide (ABR 239229)

DCM (10 mL) a N- [(trifluoromethyl) 10,11-dichloro-4-oxo-3-stirred during -2,5,7- triaza-tricyclo - [6.4.0.0 ^2,6] Pyridine-4-carboxamide hydrochloride (75 mg, 0.16 mmol) in dichloromethane (10 ml) under nitrogen was added 3-methylbutanoyl Chloride (23 mg, 0.19 mmol) was added followed by the addition of triethylamine (42 [mu] L, 0.32 mmol). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with DCM (25 mL) and rinsed with water (3 x 25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (high pH method) to give the title compound as a pale yellow solid in about 73% purity (29 mg, 35%). The title compound was tested by biological analysis without further purification.

Example 46

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -1- (3,3,3-trifluoropropanoyl) piperidine- 239232)

DCM (10 mL) a N- [(trifluoromethyl) 10,11-dichloro-4-oxo-3-stirred during -2,5,7- triaza-tricyclo - [6.4.0.0 ^2,6] 3-yl] piperidine-4-carboxamide hydrochloride (75 mg, 0.16 mmol) in tetrahydrofuran -Trifluoropropanoyl chloride (28 mg, 0.19 mmol) was added followed by triethylamine (42 L, 0.32 mmol). The solution was stirred at room temperature for 4 hours and then further 3,3,3-trifluoropropanoyl chloride (28 mg, 0.19 mmol) was added. After stirring for an additional 8 hours, the reaction mixture was diluted with DCM (20 mL) and rinsed with water (3 x 25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The reaction crude was purified by automated reverse phase HPLC (low pH method A) to give the desired product as a white solid (5 mg, 6%).

Example 47

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] azetidine-3- carboxamide (ABR 239257)

To a stirred solution of tert -butyl 3 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^{2 , 6]} dodeca-1 (12), 6,8,10- tetraen-3-yl] carbamoyl} azetidin-1-carboxylate (800 mg, 1.57 mmol) at 0 ℃ TFA (3.53 solution mL, 4.72 mmol) was added dropwise. The solution was stirred at 0 ° C for 1 hour and then allowed to warm to room temperature. After 3 hours, the reaction mixture was evaporated to about 15 mL and then diethyl ether (50 mL) was added. The suspension was concentrated and the resulting solid was azeotropically mixed three more times with diethyl ether. The solids were rinsed with MeOH / DCM (1: 1) to free base through an SCX column and then eluted with 2M ammonia in MeOH. The basic filtrate was collected and concentrated to give the title compound as a white solid (507 mg, 79%).

Example 48

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -1- (ethanesulfonyl) azetidine- 3- carboxamide (ABR 239402)

In anhydrous THF (5 mL) a N- [(trifluoromethyl) 10,11-dichloro-4-oxo-3-stirred during -2,5,7- triaza-tricyclo - [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] azetidine- (50 mg, 0.12 mmol) in dichloromethane (5 mL) was added ethanesulfonyl chloride (13 L, 0.13 mmol) followed by 2 M NaOH (aq) (92 L, 0.18 mmol). The reaction mixture was stirred at room temperature for 2 hours. Ethanesulfonyl chloride (13 L, 0.13 mmol) was further added followed by 2 M NaOH (aq) (92 L, 0.18 mmol). The reaction mixture was stirred for 2 hours and then concentrated. The residue was dissolved in EtOAc (100 mL) and rinsed with water (2 x 25 mL) and brine (50 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (31 mg, 51%).

Example 49

1-acetyl- N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] - dodeca-1 (12), 6,8,10-tetraen-3-yl] azetidine- 3- carboxamide (ABR 239403)

DCM (10 mL) a N- [(trifluoromethyl) 10,11-dichloro-4-oxo-3-stirred during -2,5,7- triaza-tricyclo - [6.4.0.0 ^2,6] To a solution of dodeca-1 (12), 6,8,10-tetraen-3-yl] azetidine-3-carboxamide (100 mg, 0.25 mmol) in acetonitrile Then triethylamine (49 [mu] L, 0.37 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was rinsed with water (2 x 25 mL) and the organic layer was concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) and azeotropically mixed to give the title compound as a white solid (19 mg, 17%).

Example 50

(rac). &lt; RTI ID = 0.0 &gt; 1-Cyclopentanecarbonyl- N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] pyrrolidine-3- carboxamide (ABR 239137)

N- [10,11--dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triaza-tricyclo stirring in DCM (3 mL) - [6.4.0.0 2,6] Pyrrolidine-3-carboxamide hydrochloride (95 mg, 0.21 mmol) in dichloromethane (5 mL) at 0 ° C was added cyclopentanecarbonyl chloride (26 L, 0.22 mmol) was added dropwise and then triethylamine (58 L, 0.41 mmol) was added dropwise under nitrogen. The reaction mixture was warmed to room temperature and stirred for an additional 16 hours. The reaction mixture was diluted with water (20 mL) and DCM (20 mL) and layer separated. Rinse the organic phase with water (20 mL), dried (MgSO ₄₎ and filtered, and then concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a mixture of diastereomers (5 mg, 5%). It was tested without further purification.

Example 51

(3R) -1- (cyclopentanesulfonyl) - N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] pyrrolidine-3- carboxamide (ABR 239139)

Stirring in THF (20 mL) (3R) - N- [( trifluoromethyl) 10,11-dichloro-4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6 ] dodeca-1 (8), 6,9,11-tetraen-3-yl] pyrrolidine-3-carboxamide hydrochloride (817 mg, 1.78 mmol) was added cyclopentanesulfonyl chloride (258 [mu] L, 1.96 mmol) followed by the addition of 2 M NaOH _(aq) (1.83 mL, 3.66 mmol). The reaction mixture was stirred at room temperature for 3 hours. Cyclopentane-sulfonyl chloride (70 [mu] L, 0.53 mmol) was further added and stirring continued for 16 hours. The reaction mixture was then concentrated and partitioned with EtOAc (50 mL) and water (50 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 0-10% MeOH in DCM as eluent to afford the title compound as an off-white solid (304 mg, 31%).

Example 52

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -1- (pyridin- 2- yl) azetidine- 3- carboxamide (ABR 239404)

To a solution of N- [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] dodeca Azetidine-3-carboxamide (100 mg, 0.25 mmol) and potassium carbonate (51 mg, 0.37 mmol) in dichloromethane . 2-Chloropyridine (28 [mu] L, 0.29 mmol) was added to the suspension and the reaction mixture was stirred at 120 [deg.] C for 16 h. The reaction mixture was concentrated and partitioned with EtOAc (25 mL) and water (25 mL). Rinse the organic phase with water (3 x 25 mL) and Dublin (2 x 25 mL), dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the desired product as a white solid (18 mg, 15%) as the formate salt.

Example 53

3-cyclohexyl -N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239034)

Tricyclo [6.4.0.0 &lt; ^2,6 &gt;] dodeca-1 (12), 6, Tetraen-4-yl] benzamide, but using 5,6-dichloro-1H-1,3-benzodiazole-2-amine with 1H-1,3-benzodiazole -2-amin e, 3-cyclohexylpropanamide was used in place of 2-bromobenzamide. The crude product was purified by silica chromatography using 2.5% MeOH in DCM as eluent (6%).

Example 54

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] cyclopentanecarboxamide (ABR 239114)

2-bromo-N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-4-yl] benzamide, the following modification was added. In the first reaction step, to prepare the acylimine intermediate product, cyclopentanecarboxamide was used in place of 2-bromobenzamide, and after addition of thionyl chloride the reaction mixture was stirred for 2.5 hours, not 16 hours. In the second reaction step, 5,6-dichloro-1H-1,3-benzodiazol-2-amine was used in place of 1H-1,3-benzodiazole- Lt; / RTI &gt; The crude product was purified by silica chromatography using 2% MeOH in DCM as eluent (9%).

Example 55

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] cyclohexanecarboxamide (ABR 239115)

2-bromo-N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-4-yl] benzamide, the following modification was added. In the first reaction step, to prepare the acylimine intermediate product, cyclohexanecarboxamide was used in place of 2-bromobenzamide, and after the addition of thionyl chloride, the reaction mixture was stirred for 2.5 hours instead of 16 hours. In the second reaction step, 5,6-dichloro-1H-1,3-benzodiazol-2-amine was used in place of 1H-1,3-benzodiazole- Lt; / RTI &gt; The crude product was purified by silica chromatography using 3% MeOH in DCM as eluent and then tritylated in DCM / pentane (2%).

Example 56

3-chloro -N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (12), 6,8,10-tetraen-3-yl] benzamide (ABR 239414)

2-bromo-N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-4-yl] benzamide, the following modification was added. In the first reaction step, 3-chlorobenzamide was used in place of 2-bromobenzamide to prepare the acylimine intermediate, and the reaction mixture was stirred for 18 hours instead of 16 hours after addition of thionyl chloride. In the second reaction step, 5,6-dichloro-1H-1,3-benzodiazol-2-amine was used in place of 1H-1,3-benzodiazole- Stir for 18 hours. The crude product was purified by silica chromatography using 2 - 4% MeOH in DCM as eluent (3%).

Example 57

3,5-dichloro -N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] benzamide (ABR 239427)

2-bromo-N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-4-yl] benzamide, the following modification was added. In the first reaction step, 3,5-dichlorobenzamide was used in place of 2-bromobenzamide to prepare the acylimine intermediate product, and after the addition of thionyl chloride the reaction mixture was stirred for 18 hours instead of 16 hours Respectively. In the second reaction step, 5,6-dichloro-1H-1,3-benzodiazol-2-amine was used instead of 5,6-dimethyl-1H-1,3-benzodiazole- , And the reaction was stirred for 18 hours instead of 4 hours. The crude product was purified by silica chromatography using 4% MeOH in DCM as eluent (5%).

Example 58

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -4- (pyrrolidin- 1- yl) butanamide (ABR 239155)

2-bromo-N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-4-yl] benzamide, the following modification was added. In the first reaction step, 4- (pyrrolidin-1-yl) butanamide was used in place of 2-bromobenzamide to prepare the acylimine intermediate product, and after the addition of thionyl chloride the reaction mixture was stirred for 16 h Instead of stirring for 72 hours. In the second reaction step, 5,6-dichloro-1H-1,3-benzodiazol-2-amine was used in place of 1H-1,3-benzodiazole- Lt; / RTI &gt; The crude product was purified by automated reverse phase HPLC (low pH method B) (1%).

Example 59

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -4- (morpholin-4-yl) butanamide (ABR 239161)

2-bromo-N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-4-yl] benzamide, the following modification was added. In the first reaction step, 4- (morpholin-4-yl) butanamide was used in place of 2-bromobenzamide to prepare the acylimine intermediate product, and the reaction mixture after the addition of thionyl chloride And the mixture was stirred for 2.5 hours. In the second reaction step, 5,6-dichloro-1H-1,3-benzodiazol-2-amine was used in place of 1H-1,3-benzodiazole- Lt; / RTI &gt; The crude product was purified by silica chromatography using 20% MeOH in DCM as eluent (11%).

Example 60

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2- (morpholin- 4- yl) acetamide (ABR 239358)

2-bromo-N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-4-yl] benzamide, the following modification was added. In the first reaction step, 2- (morpholin-4-yl) acetamide (prepared according to literature (Chaudhari et al. 2007)) was used instead of 2-bromobenzamide to prepare the acylimine intermediate product , And after addition of thionyl chloride, the reaction mixture was stirred for 18 hours instead of 16 hours. In the second reaction step, 5,6-dichloro-1H-1,3-benzodiazol-2-amine was used in place of 1H-1,3-benzodiazole- Lt; / RTI &gt; The crude product was purified by automated reversed phase HPLC (low pH method B) (4%).

Example 61

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (morpholin- 4- yl) propanamide (ABR 239259)

To a solution of 2 - [(5,6-dichloro-1H-1,3-benzodiazol-2-yl) amino] -3,3,3-trifluoro- Trimethylaluminum (75 L, 0.39 mmol) was added dropwise at 0 &lt; 0 &gt; C under argon to a solution of 4-amino-3- The reaction was warmed to room temperature, stirred at room temperature for 1 hour and then heated at 100 &lt; 0 &gt; C for 16 hours. The reaction was cooled to room temperature and ice water was added. The precipitate formed was filtered off and the filtrate was extracted with EtOAc (2 x 20 mL). The combined organic phases were evaporated, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica chromatography using 4% MeOH in DCM as eluent to afford the title compound as a gray solid (15 mg, 8%).

Example 62

6-chloro -N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] - dodeca-1 (12), 6,8,10-tetraen-3-yl] pyridine- 2- carboxamide (ABR 239356)

2-bromo-N- [3-oxo-4- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-4-yl] benzamide, the following modification was added. In the first reaction step, 6-chloropyridine-2-carboxamide was used instead of 2-bromobenzamide to prepare the acylimine intermediate product. In the second reaction step, 5,6-dichloro-1H-1,3-benzodiazol-2-amine was used in place of 1H-1,3-benzodiazole- Lt; / RTI &gt; The crude product was purified by silica chromatography using 2% MeOH in DCM as eluent (14%).

Example 63

6- (Azetidin-1-yl) -N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] - dodeca-1 (12), 6,8,10-tetraen-3-yl] pyridine- 2- carboxamide (ABR 239354)

DMF (3 mL), 6- chloro -N- [(trifluoromethyl) 10,11-dichloro-4-oxo-3- -2,5,7- triaza-tricyclo [6.4.0.0 ^{2, 6]} dodeca-1 (12), 6,8,10- tetraen-3-yl] pyridine-2-carboxamide (200 mg, 0.43 mmol) solution, in a sealed tube, K ₂ CO ₃ ( 59 mg, 0.43 mmol) and azetidine (25 mg, 0.43 mmol). The reaction mixture was heated at 100 &lt; 0 &gt; C for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 25 mL). The organic phases were combined, rinsed with brine (15 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method B) to give the title compound as a white solid (70 mg, 33%).

Example 64

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -6- (2,2,2- trifluoroethoxy) pyridine- 2- carboxamide (ABR 239390)

6- (Azetidin-l-yl) -N- [10,11-dichloro-4-oxo-3- (trifluoro- methyl) -2,5,7- triazatricyclo [6.4.0.0 ^{2 , 6} ] dodeca-1 (12), 6,8,10-tetraen-3-yl] pyridine-2-carboxamide was used but 2,2,2-trifluoroethane- -Ol was used instead of azetidine (15%).

Example 65

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -6- (dimethylamino) pyridine- 2- carboxamide (ABR 239391)

N- [10,11- dichloro (trifluoromethyl) -4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca-1 (12), 6 , 8,10-tetraen-3-yl] -6- (dimethylamino) pyridine-2-carboxamide was used but dimethylamine (70 wt.% Aqueous solution) was used instead of azetidine (52%).

Example 66

6- (cyclohexylamino) -N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] pyridine-2- carboxamide (ABR 239409)

N- [10,11- dichloro (trifluoromethyl) -4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca-1 (12), 6 , 8,10-tetraen-3-yl] -6- (dimethylamino) pyridine-2-carboxamide was used but cyclohexylamine was used instead of azetidine, And heated for 2 hours. The crude product was purified by silica chromatography, eluting with 3% MeOH in DCM as eluent and then recrystallizing in DCM / MeOH to give the title compound (31%).

Example 67

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -6- (ethylamino) pyridine- 2- carboxamide (ABR 239101)

To a sealed tube was added 6-chloro- N- [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Carboxamide (150 mg, 0.35 mmol) and ethylamine (70 wt.% Aqueous solution, 56 μl, 1.06 mmol) were added to a solution of 2- Lt; / RTI &gt; The reaction was heated at 100 &lt; 0 &gt; C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 25 mL). The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method B) to give the title compound as a white solid (31 mg, 20%).

Example 68

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] (12), 6,8,10-tetraen-3-yl] -2- (piperidin-4-yl) acetamide (ABR 239386)

A 4M solution of HCl in dioxane (3 mL, 12.0 mmol) was added to a solution of tert -butyl 4 - ({[10,11 -dichloro-4-oxo-3- (trifluoromethyl) tricyclo [6.4.0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] carbamoyl} methyl) piperidine-1-carboxylate (60 mg, 0.11 mmol) at 0 &lt; 0 &gt; C. The reaction mixture was stirred at room temperature for 3 hours and concentrated. The residue was triturated in diethyl ether / EtOH to give the title compound as a white solid with hydrochloride salt (41 mg, 77%).

Example 69

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (piperidin- 2- yl) propanamide (ABR 239393)

A solution of 4M HCl in dioxane (5 mL, 20.0 mmol) was added to a solution of tert -butyl 2- (2 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) azatricyclo [6.4.0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] carbamoyl} ethyl) piperidine-1-carboxylate (200 mg, 0.35 mmol) at 0 &lt; 0 &gt; C. The reaction mixture was stirred at room temperature for 3 hours and concentrated. The residue was triturated in diethyl ether / EtOH to give the title compound as an off-white solid as a hydrochloride salt (140 mg, 60%).

Example 70

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -6- (ethylamino) pyridine- 2- carboxamide (ABR 239355)

EtOH (20 mL) of 6-Chloro -N- [10,11--dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^{2, 6} ] dodeca-1 (12), 6,8,10-tetraen-3-yl] pyridine-2- carboxamide (2.00 g, 4.31 mmol) in a sealed tube, Hydrate (722 mg, 4.31 mmol) and 2M ethylamine / THF (194 mg, 4.31 mmol). The reaction was heated at 100 &lt; 0 &gt; C for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 25 mL). The combined organic phases were rinsed with brine (15 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method B) to give the title compound as an orange solid (172 mg, 8%).

Example 71

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -6 - [(2- methoxyethyl) amino] pyridine- 2- carboxamide (ABR 239432)

To a solution of N- [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] dodeca (150 mg, 0.33 mmol) in a sealed tube was added K ₂ CO _{3 ( 2} ml) in a sealed tube, to a solution of 2-fluoro-pyridin- (93 mg, 0.67 mmol) and 2-methoxyethan-l-amine (25 mg, 0.34 mmol). The reaction mixture was heated at 100 &lt; 0 &gt; C for 2 hours. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 25 mL). The combined organic phases were rinsed with brine (15 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method B) to give the title compound as an off-white solid (35 mg, 21%).

Example 72

N- [10,11-Difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] benzamide (ABR 238928)

To a stirred solution of 5,6-difluoro-1H-1,3-benzodiazol-2-amine (60 mg, 0.35 mmol) in DMF (2 mL) was added methyl (Z) -benzoylimino- 3,3-Trifluoropropanoate (92 mg, 0.35 mmol) and triethylamine (47 L, 0.35 mmol) were added under nitrogen. The solution was stirred at room temperature for 3 hours and then concentrated. The residue was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a yellow solid (39 mg, 28%).

Example 73

3-Cyclopentyl- N- [10,11-Difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 238925)

To a stirred solution of 5,6-difluoro-lH-l, 3-benzodiazole-2-amine (100 mg, 0.59 mmol) and methyl (2Z) -2- [ (79 mg, 0.59 mmol) was added under nitrogen to a solution of 2-amino-2-methyl-propanoyl) imino] -3,3,3-trifluoropropanoate (165 mg, 0.59 mmol). The reaction mixture was further stirred at room temperature for 4 hours, then concentrated and purified by automated reverse phase HPLC (low pH method A) to give the title compound as an off-white solid (44 mg, 18%).

Example 74

2-Cyclohexyl- N- [10,11-Difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] - dodeca-1 (8), 6,9,11-tetraen-3-yl] acetamide (ABR 238929)

To a stirred solution of 5,6-difluoro-lH-l, 3-benzodiazol-2-amine (75 mg, 0.44 mmol) and methyl (2Z) -2 - [(2-cyclohexyl Acetyl) imino] -3,3,3-trifluoropropanoate (124 mg, 0.44 mmol) in tetrahydrofuran (20 mL) was added triethylamine (59 L, 0.44 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the desired product as a beige solid (85 mg, 46%).

Example 75

N- [10,11-Dimethoxy-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] benzamide (ABR 238995)

Dimethoxy-1H-1,3-benzodiazol-2-amine (100 mg, 0.52 mmol) and methyl (Z) -benzoylimino- To a solution of 3-trifluoropropanoate (134.15 mg, 0.52 mmol), triethylamine (68.91 l, 0.52 mmol) was added under nitrogen. The reaction mixture was stirred at room temperature for 16 hours and then concentrated. The residue was purified by automated reverse phase HPLC (low pH method A) and then triturated in MeOH to give the title compound as an off-white solid (15 mg, 7%).

Example 76

3-Cyclopentyl- N- [10,11-Dimethoxy-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 238927)

To a stirred solution of 5,6-dimethoxy-1H-1,3-benzodiazole-2-amine (100 mg, 0.52 mmol) and methyl (2Z) -2- [ (69 μl, 0.52 mmol) was added under nitrogen to a solution of 2-amino-2-methyl-propanoyl) imino] -3,3,3-trifluoropropanoate (145 mg, 0.52 mmol). The reaction mixture was stirred for 4 hours and then concentrated. The residue was purified by automated reverse phase HPLC (low pH method A) and then triturated with ether to give the title compound as a yellow solid (31 mg, 14%).

Example 77

N- [9-Bromo-10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] benzamide (ABR 239170)

DCM (trifluoromethyl) the N- [10,11- dimethyl-4-oxo-3-stirred during the (5 mL) -2,5,7- triaza-tricyclo - [6.4.0.0 ^2,6] N -bromosuccinimide (39 mg, 0.22 mmol) was added to a solution of dodeca-1 (8), 6,9,11-tetraen-3- ylbenzamide (84 mg, 0.22 mmol) Lt; / RTI &gt; The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (20 mL) and rinsed with water (2 x 20 mL). The organic phase was concentrated and purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (41 mg, 41%).

Example 78

3-Cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3.7 .0 ^10,14 ] -Pentadeca-1 (9), 2,7,14-tetraen-11-yl] propanamide (ABR 239320)

Methyl 3,3,3-trifluoro-2-oxopropanoate (72 L, 0.71 mmol) was added to a stirred solution of 3-cyclopentylpropanamide (93 mg, 0.57 mmol) in DMF Then pyridine (57 [mu] L, 0.71 mmol) was added at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. Thionyl chloride (51 [mu] L, 0.71 mmol) was added at 0 [deg.] C and then the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was filtered through a silica short pad eluting with DCM (50 mL) and under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (2 mL) under nitrogen. Amine (98 mg, 0.57 mmol) and triethylamine (113 L, 0.85 mmol) were added to the reaction mixture, and the reaction mixture was stirred at room temperature Stir for 18 hours. The reaction mixture was diluted with EtOAc (20 mL) and rinsed with water (4 x 10 mL) and brine (10 mL). The organic phase was dried (Na ₂ SO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 50% EtOAc in heptane as eluent to give the title compound as a white solid (66 mg, 28%).

Example 79

N- [10-chloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide and

N- [11-chloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239329)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- Chloro-1H-1,3-benzodiazole-2-amine was synthesized in the same manner as 1H, 5H, 6H, 7H - indeno [5,6-d] imidazol-2-amine. The crude product was purified by minimal trafficking in DCM to give DCM, the title compound as a 1: 1 mixture of positional isomers (34%).

Example 80

3-Cyclopentyl- N- [9,10-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239330)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- ), 2,7,14-tetraen-11-yl] propan-amide but using 4,5-dimethyl-1H-1,3-benzodiazole- 6H, 7H-indeno [5,6-d] imidazol-2-amine. An additional equivalent of thionyl chloride was added at 0 &lt; 0 &gt; C for 1 h after the first addition, and then the reaction was stirred at room temperature for 1 h and then concentrated. The crude product was purified by trituration in a minimal amount of DCM to give the title compound (38%).

Example 81

3-Cyclopentyl- N- [9-methyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239343)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- 4-methyl-1H-1,3-benzodiazole-2-amine was synthesized in the same manner as 1H, 5H, 6H, 7H - indeno [5,6-d] imidazol-2-amine. The crude product was purified by trituration in a minimal amount of DCM to give the title compound (17%).

Example 82

3-Cyclopentyl- N- [9, 10-Difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239371)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- ), 2,7,14-tetraen-11-yl] propan-amide but using 4,5-difluoro-1H-1,3-benzodiazole- , 6H, 7H-indeno [5,6-d] imidazol-2-amine. The crude product was purified by minimal trafficking in DCM to give the title compound (33%).

Example 83

3-Cyclopentyl- N- [9,10-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239375)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- ), 2,7,14-tetraen-11-yl] propan-amide but using 4,5-dichloro-1H-1,3-benzodiazole- 6H, 7H-indeno [5,6-d] imidazol-2-amine. The crude product was purified by trituration in a minimal amount of DCM to give the title compound (28%).

Example 84

3-Cyclopentyl- N- [9,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239394)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- Yl) propane-amide but using 4,6-dichloro-1H-1,3-benzodiazole-2-amine in the form of 1H, 5H, 6H, 7H-indeno [5,6-d] imidazol-2-amine. An additional equivalent of thionyl chloride was added at 0 &lt; 0 &gt; C after 1 h after the first addition, then the reaction was stirred at room temperature for 1 h and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound (27%).

Example 85

N- [9-chloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239399)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- Chloro-1H-1,3-benzodiazole-2-amine was synthesized in the same manner as 1H, 5H, 6H, 7H - indeno [5,6-d] imidazol-2-amine. An additional equivalent of thionyl chloride was added at 0 &lt; 0 &gt; C for 1 h after the first addition, then the reaction was stirred at room temperature for 1 h and concentrated. The crude product was purified by trituration in a minimal amount of DCM to give the title compound (19%).

Example 86

3-Cyclopentyl- N- [9, 11-Difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239422)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- ), 2,7,14-tetraen-11-yl] propan-amide was used, but 4,6-difluoro-1H-1,3-benzodiazole- , 6H, 7H-indeno [5,6-d] imidazol-2-amine. The crude product was purified by silica chromatography using 44% EtOAc in heptane as eluent and then triturated in a minimal amount of DCM to give the title compound (11%).

Example 87

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] oxane-4-carboxamide (ABR 239441)

To a stirred solution of oxane-4-carboxamide (500 mg, 3.87 mmol) in DMF (15 mL) was added pyridine (312 L, 3.87 mmol) followed by ethyl 3,3,3-trifluoro- Oxopropanoate (658 mg, 3.87 mmol) was added at room temperature under argon. The reaction mixture was stirred at room temperature for 1 hour and then thionyl chloride (422 [mu] L, 5.81 mmol) was added. The reaction was stirred for an additional 16 h and then concentrated. The remaining acyl intermediate was dissolved in DMF (5 mL) under argon. A solution of 5,6-dichloro-1H-1,3-benzodiazole-2-amine (587 mg, 2.90 mmol) in DMF (7 mL) and triethylamine (861 L, 6.19 mmol) The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 15 mL). Rinse the combined organic extracts were Dublin, dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography. Further purification by trituration in DCM / MeOH followed by pentane afforded the title compound (20 mg, 1%).

Example 88

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 (8), 6,9,11-tetraen-3-yl] -3- (1-hydroxycyclopentyl) propanamide (ABR 239702)

A solution of cyclopentanone (234 μL, 2.63 mmol) and DMPU (127 μL, 1.05 mmol) in anhydrous degassed THF (30 mL) and MeOH (3 mL) was stirred at 0 ° C. under nitrogen. To a solution of N- [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5 (trifluoromethyl) pyridine in 0.1 M samarium iodide solution in THF (10.55 mL, 1.06 mmol) and anhydrous THF , 7-triaza-tricyclo [6.4.0.O ^2,6] dodeca-1 (8), 6,9,11- tetraen-3-yl] prop-2-en-amide (100 mg, 0.26 mmol) was added dropwise at the same time over 10 minutes. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 20 min. The reaction was poured into cold water (100 mL) and extracted with EtOAc (3 x 50 mL). The organic phases were combined and rinsed with 1 M HCl _(aq) and brine (2 x 50 mL), then dried (MgSO ₄ ), filtered and concentrated. The compound crude was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (22 mg , 18%).

Example 89

Diastereomer 1: (2S) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -1-methanesulfonylpyrrolidine-2- carboxamide (ABR 239679

To a stirred solution of (2S) -1-methanesulfonylpyrrolidine-2-carboxamide (400 mg, 2.08 mmol) in DMF (6 mL) was added methyl 3,3,3-trifluoro- (320 [mu] L, 3.13 mmol) was added followed by pyridine (170 [mu] L, 2.08 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 19 hours. Thionyl chloride (150 [mu] L, 2.08 mmol) was added at 0 [deg.] C and the reaction was stirred for 1 hour. The reaction mixture was concentrated, and the residue was eluted through a silica short pad with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (5 mL) under nitrogen. A solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (280 mg, 1.74 mmol) in DMF (5 mL) and triethylamine (280 L, 2.08 mmol) was added. The reaction mixture was stirred at room temperature for 17 hours and then concentrated. The residue was diluted with EtOAc (40 mL) and rinsed with water (2 x 30 mL), 10% citric acid _(aq) (2 x 20 mL) and brine (20 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by trituration in DCM to give a clear diastereomeric mixture. The diastereomeric mixture was purified by automated reversed-phase HPLC (low pH method A) to give diastereoisomer 1 as a white solid as a single diastereomer, of which the stereochemistry was not defined at the quarter center (82 mg , 10%).

Example 90

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 (8), 6,9,11-tetraen-3-yl] -6- [(3-methoxypropyl) amino] pyridine- 2- carboxamide (ABR 239523)

To a solution of N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca- To a solution of 1 (12), 6,8,10-tetraen-3-yl] -6-fluoropyridine-2- carboxamide (250 mg, 0.56 mmol) in a sealed tube was added K ₂ CO ₃ 185 mg, 1.34 mmol) and 3-methoxypropan-l-amine (62 mg, 0.70 mmol). The reaction mixture was heated at 100 &lt; 0 &gt; C for 4 hours. Additional 3-methoxypropan-l-amine (62 mg, 0.70 mmol) was added. The reaction was heated at 100 &lt; 0 &gt; C for another 8 hours and then concentrated. The residue was dissolved in EtOAc (50 mL) and rinsed with water (3 x 25 mL) and brine (3 x 25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The compound crude was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a yellow oil (35 mg, 12%).

Example 91

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 (8), 6,9,11-tetraen-3-yl] -6- [(2-hydroxyethyl) amino] pyridine- 2- carboxamide (ABR 239539)

To a solution of N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca- To a solution of 1 (12), 6,8,10-tetraen-3-yl] -6-fluoropyridine-2-carboxamide (100 mg, 0.22 mmol) in a sealed tube was added K ₂ CO ₃ 74 mg, 0.54 mmol) and 2-aminoethan-1-ol (27 mg, 0.45 mmol). The reaction mixture was heated at 100 &lt; 0 &gt; C for 18 h and then concentrated. The residue was dissolved in EtOAc (50 mL) and rinsed with water (3 x 25 mL) and brine (3 x 25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The compound crude was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a yellow oil (51 mg, 47%).

Example 92

Diastereomeric mixture. N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6 - {[(2S) -1- methoxypropan-2- yl] amino} pyridine- (ABR 239540)

To a solution of N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca- To a solution of 1 (12), 6,8,10-tetraen-3-yl] -6-fluoropyridine-2-carboxamide (100 mg, 0.22 mmol) in a sealed tube was added K ₂ CO ₃ 74 mg, 0.54 mmol) and (2S) -1-methoxypropan-2-amine (40 mg, 0.45 mmol). First, the reaction mixture was heated at 100 DEG C for 16 hours. The reaction was then heated for a further 20 hours. During this period additional (2S) -1-methoxypropan-2-amine (80 mg, 0.90 mmol) and K ₂ CO ₃ (74 mg, 0.54 mmol) . The reaction was then concentrated. The residue was dissolved in EtOAc (50 mL) and rinsed with water (3 x 25 mL) and brine (2 x 25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The compound crude was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a yellow solid (15 mg, 13%) as a mixture of diastereomers.

Example 93

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 (8), 6,9,11-tetraen-3-yl] -6- {[2- (dimethylamino) ethyl] amino} pyridine-2- carboxamide (ABR 239587)

To a solution of N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca- To a solution of 1 (12), 6,8,10-tetraen-3-yl] -6-fluoropyridine-2-carboxamide (100 mg, 0.22 mmol) in a sealed tube was added K ₂ CO ₃ 93 mg, 0.67 mmol) and (2-aminoethyl) dimethylamine (59 mg, 0.67 mmol). The reaction mixture was heated at 100 &lt; 0 &gt; C for 16 h and then concentrated. The residue was dissolved in EtOAc (50 mL) and rinsed with water (2 x 25 mL) and brine (2 x 25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The compound crude was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a pink solid (38 mg, 33%) as the formic acid salt.

Example 94

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 (8), 6,9,11-tetraen-3-yl] -6- [(2-methoxyethyl) (methyl) amino] pyridine- 2- carboxamide (ABR 239537)

To a solution of 6 - [(2-methoxyethyl) (methyl) amino] pyridine-2-carboxamide (571 mg, 2.73 mmol) in DMF (10 mL) was added methyl 3,3,3-trifluoro -2-oxopropanoate (852 mg, 5.46 mmol) was added followed by pyridine (220 L, 2.73 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. Thionyl chloride (198 [mu] L, 2.73 mmol) was added at 0 [deg.] C and then the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was eluted through a silica short pad with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (10 mL) under nitrogen. (441 mg, 2.18 mmol) and triethylamine (381 [mu] L, 2.72 mmol) were added and the reaction mixture was stirred at room temperature for 2 hours Respectively. The reaction mixture was concentrated. The residue was dissolved in EtOAc (100 mL) and rinsed with water (3 x 50 mL) and brine (3 x 50 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 0-10% MeOH in DCM as eluent. Further purification by automated reverse phase HPLC (high pH) gave the title compound as a yellow solid (24 mg, 2%).

Example 95

Methyl 6 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] carbamoyl} pyridine- 2- carboxylate (ABR 239572)

To a stirred solution of methyl 6-carbamoylpyridine-2-carboxylate (1.00 g, 5.55 mmol) in DMF (15 mL) was added methyl 3,3,3-trifluoro-2-oxopropanoate (1.14 mL, 11.11 mmol) followed by pyridine (450 [mu] L, 5.55 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1.5 hours. Thionyl chloride (405 [mu] L, 5.55 mmol) was added at 0 [deg.] C, then the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated, and the residue was eluted through a silica short pad with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (15 mL) under nitrogen. (935 mg, 4.63 mmol) and triethylamine (739 [mu] L, 5.55 mmol) were added and the reaction mixture was stirred at room temperature for 20 hours Respectively. The reaction mixture was concentrated. The residue was diluted with EtOAc (50 mL) and rinsed with water (3 x 50 mL) and brine (2 x 50 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 0-3% MeOH in DCM as eluent to give the title compound as a brown oil (35 mg, 2%).

Example 96

2- N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6- N- (2-methoxyethyl) pyridine-2,6-dicarboxamide (ABR 239588)

2-methoxyethan-l-amine (13 l, 0.15 mmol) was added to a solution of 1,4-diazabicyclo [2.2.2] octane- trimethylaluminum (1: 2, 39 mg, 0.15 mmol) under nitrogen. The reaction was heated at 40 &lt; 0 &gt; C for 30 minutes. Methyl-6 in THF (0.5 mL) - {[ 10,11- -dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca Carboxylate (50 mg, 0.1 mmol) in DMF (10 mL) was then added and the reaction was stirred at 70 &lt; 0 &gt; C for 16 h And heated. Diazabicyclo [2.2.2] octane-trimethylaluminum (1: 2, 39 mg, 0.15 mmol) and 2-methoxyethan- 1 -amine (13 L, 0.15 mmol) The reaction was further heated at 70 &lt; 0 &gt; C for 4 h. The reaction was quenched by adding cold water, and rinsed with EtOAc (3 x 10 mL). The aqueous phase was acidified with 10% citric acid _(aq) (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were rinsed with brine (2 x 25 mL), dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (high pH) to give the title compound as a brown solid (13 mg, 15%).

Example 97

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6- (hydroxymethyl) pyridine- 2- carboxamide (ABR 239602)

Sodium tetrahydroborate (110 mg, 2.87 mmol) was added to a stirred solution of methyl 6 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) ) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (8), 6,9,11-tetraen-3- yl] carbamoyl} pyridine- (200 mg, 0.41 mmol) at O &lt; 0 &gt; C. The reaction was stirred for 24 hours. Further sodium tetrahydroborate (220 mg, 5.74 mmol) was added in portions at 0 &lt; 0 &gt; C over 40 h. The reaction was quenched by dropwise addition of saturated NH ₄ Cl _(aq) , diluted with water and acidified using 10% citric acid _(aq) . The phases were extracted with EtOAc (3 x 25 mL). Dry the combined organic extracts (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (neutral pH) to give the title compound as a white solid (35 mg, 19%).

Example 98

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-fluorobenzamide (ABR 239440)

To a stirred solution of 3-fluorobenzamide (500 mg, 3.59 mmol) in DMF (5 mL) was added pyridine (306 L, 3.59 mmol) followed by ethyl 3,3,3-trifluoro- Propanoate (476 [mu] L, 3.59 mmol) was added at room temperature under argon. The reaction mixture was stirred at room temperature for 1 hour. Thionyl chloride (231 [mu] L, 3.18 mmol) was added at 0 [deg.] C and then the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated. The remaining acyl intermediate was dissolved in DMF (2 mL) under argon. (545 mg, 2.70 mmol) and triethylamine (503 [mu] L, 3.59 mmol) were added and the reaction mixture was stirred at room temperature for 16 h Lt; / RTI &gt; The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was rinsed with brine then dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica chromatography using 3% MeOH in DCM as eluent. Further purification by trituration in DCM / MeOH followed by pentane afforded the title compound as an off-white solid (22 mg, 1%).

Example 99

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3,5-difluorobenzamide (ABR 239446)

To a stirred solution of 3,5-difluorobenzamide (500 mg, 3.18 mmol) in DMF (5 mL) was added pyridine (271 L, 3.18 mmol) followed by ethyl 3,3,3- 2-oxopropanoate (422 [mu] L, 3.18 mmol) was added at room temperature under argon. The reaction mixture was stirred at room temperature for 1 hour. Thionyl chloride (231 [mu] L, 3.18 mmol) was added at 0 [deg.] C. The reaction mixture was stirred at room temperature for 16 hours and then the reaction mixture was concentrated. The remaining acyl intermediate was dissolved in DMF (2 mL) under argon. (482 mg, 2.39 mmol) and triethylamine (668 [mu] L, 4.77 mmol) were added and the reaction mixture was stirred at room temperature for 4 hours Respectively. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was rinsed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica chromatography using 3% MeOH in DCM as eluent. Further purification by trituration from DCM / MeOH and subsequent pentane gave the title compound as an off-white solid (20 mg, 1%).

Example 100

3-cyano- N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] benzamide (ABR 239453)

To a stirred solution of 3-cyanobenzamide (650 mg, 4.45 mmol) in DMF (7 mL) was added pyridine (378 L, 4.45 mmol) followed by ethyl 3,3,3-trifluoro- Propanoate (590 [mu] L, 4.45 mmol) was added at room temperature under argon. The reaction mixture was stirred at room temperature for 1 hour. Thionyl chloride (323 [mu] L, 4.45 mmol) was added at 0 [deg.] C. The reaction mixture was then stirred at room temperature for a further 16 hours and the reaction mixture was concentrated. The remaining acyl intermediate was dissolved in DMF (5 mL) under argon. (674 mg, 3.34 mmol) and triethylamine (934 [mu] L, 6.67 mmol) were added and the reaction mixture was stirred at room temperature for 16 h Lt; / RTI &gt; The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was rinsed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica chromatography using 3% MeOH in DCM as eluent. Further purification by trituration in DCM / MeOH and subsequent pentane gave the title compound as a white solid (25 mg, 1%).

Example 101

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2 - [(2- methoxyethyl) amino] -1,3-thiazole- 239601)

To a stirred solution of 2-bromo-1,3-thiazole-4-carboxamide (360 mg, 1.74 mmol) in DMF (15 mL) was added methyl 3,3,3-trifluoro- (543 mg, 3.48 mmol) was added followed by the addition of pyridine (140 L, 1.74 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. Thionyl chloride (126 [mu] L, 1.74 mmol) was added at 0 [deg.] C, then the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated and the residue was filtered through a silica short pad eluting with DCM and under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (10 mL) under nitrogen. A solution of 5,6-dichloro-lH-l, 3-benzodiazole-2-amine (293 mg, 1.45 mmol) in DMF (10 mL) and triethylamine (231 L, 1.74 mmol) The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was diluted in EtOAc (50 mL) and rinsed with 10% citric acid _(aq) (2 x 25 mL), water (2 x 25 mL) and brine (2 x 25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was triturated in DCM to give 2-bromo- N- [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4 .0.0 ^2,6] dodeca-1 (8), 6,9,11- tetraen-3-yl] -1,3-thiazol-4-carboxamide and 2-chloro - N- [10, Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (8), 6,9,11- Tetraen-3-yl] -1,3-thiazole-4-carboxamide (746 mg).

To a microwave tube was added 2-bromo- N- [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -1,3-thiazole- 4- carboxamide and 2-chloro- N- [10,11- Dioxa-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (8), 6,9,11- (80 mg), K ₂ CO ₃ (64 mg, 0.47 mmol) and 2-methoxyethan-1 -amine (40 μl, 0.47 mmol ) And dioxane (2 mL). First, the reaction was heated in a microwave for 1 hour at 130 &lt; 0 &gt; C. The reaction was then heated for a further 4 hours. During this period, additional 2-methoxyethan-1-amine (160 L, 1.88 mmol) and K ₂ CO ₃ (256 mg, 1.88 mmol) were added and added in portions during the re-treatment at room temperature. The reaction mixture was then concentrated. The residue was dissolved in EtOAc (25 mL) and rinsed with water (25 mL), 10% citric acid _(aq) (25 mL) and brine (25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (27 mg).

Example 102

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -1- (2,2-difluoroethyl) azetidine- 3- carboxamide (ABR 239437)

DMF (2 mL), N- [(trifluoromethyl) 10,11-dichloro-4-oxo-3-one was stirred in -2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca Carboxamide (75 mg, 0.18 mmol) in tetrahydrofuran (10 ml) was added 1,1-difluoro-2-iodo Ethane (39 mg, 0.20 mmol) was added followed by K ₂ CO ₃ (51 mg, 0.37 mmol). The reaction was heated at 80 &lt; 0 &gt; C for 16 h and then concentrated. The residue was dissolved in EtOAc (25 mL) and rinsed with water (2 x 25 mL) and brine (3 x 25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (11 mg, 13%) as the formic acid salt.

Example 103

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3-fluoroazetidine-3- carboxamide (ABR 239689)

To a solution of tert- butyl 3 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^{2 , 6} ] dodeca-1 (8), 6,9,11-tetraen-3-yl] carbamoyl} -3-fluoroazetidine- 1 -carboxylate (58 mg, 0.11 mmol) (1 mL) at 0 &lt; 0 &gt; C under nitrogen. The reaction was warmed to room temperature and stirred for 16 hours. The reaction mixture was then concentrated and azeotropically mixed with toluene (3 x 20 mL). The crude product was purified by automated reverse phase HPLC (high pH) to give the title compound as a white solid (11 mg, 23%).

Example 104

N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3- (3,3- difluoroazetidin- 1 -yl) propanamide (ABR 239705)

To a solution of N- [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -dodeca Propan-2-enamide (125 mg, 0.33 mmol) in a sealed tube was added 3,3-difluoroazetidine Hydrochloride (56 mg, 0.43 mmol), silica (16 mg) and triethylamine (88 [mu] L, 0.66 mmol) were added. The reaction was heated at 80 &lt; 0 &gt; C for 3 hours. The silica was filtered off and the filtrate was concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (22 mg, 14%).

Example 105

3- (3,3-Difluoroazetidin-1-yl) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] propanamide (ABR 239647)

To a solution of N- [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca- Propan-2-enamide (125 mg, 0.37 mmol) in a sealed tube was added 3,3-difluoroazetidine hydro- Chloride (62 mg, 0.48 mmol), silica (18 mg) and triethylamine (98 L, 0.74 mmol). The reaction was heated at 70 &lt; 0 &gt; C for 3 hours. The silica was filtered off and the filtrate was concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (45 mg, 28%).

Example 106

3-Cyclobutyl- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (8), 6,9,11-tetraen-3-yl] propanamide (ABR 239536)

To a stirred solution of 3-cyclobutyl propanamide (250 mg, 1.97 mmol) in DMF (20 mL) was added pyridine (159 μL, 1.97 mmol) followed by methyl 3,3,3-trifluoro- Oxo-propanoate (614 mg, 3.93 mmol) was added at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. Thionyl chloride (147 [mu] L, 1.97 mmol) was added at 0 [deg.] C and the reaction was stirred at 0 &lt; 0 &gt; C for 1 hour. The reaction mixture was concentrated and the residue was filtered through a silica short pad eluting with DCM and under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (10 mL) under nitrogen. Dimethyl-1H-1,3-benzodiazole-2-amine (254 mg, 1.57 mmol) and triethylamine (261 l, 1.97 mmol). The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was diluted with EtOAc (50 mL) and rinsed with water (3 x 50 mL) and brine (2 x 50 mL). The organic phase was dried (Na ₂ SO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 0-10% MeOH in DCM as eluent to give the title compound as a white solid (60 mg, 8%).

Example 107

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3- (1-hydroxycyclopentyl) propanamide (ABR 239578)

A solution of cyclopentanone (210 L, 2.36 mmol) and DMPU (285 L, 2.36 mmol) in anhydrous degassed THF (20 mL) and MeOH (5 mL) was stirred at 0 <0> C under nitrogen. To a solution of 0.1 M samarium iodide in THF (23.6 mL, 2.36 mmol) and N- [10,11-dimethyl-4-oxo-3- (trifluoromethyl) (8), 6,9,11-tetraen-3-yl] prop-2-enamide (200 mg, 0.59 mmol) was added to a solution of 5,7-triazatricyclo [6.4.0.0 ^2,6 ] ) Solution was added dropwise simultaneously over 10 minutes. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 20 min, then poured into cold water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were rinsed with brine (2 x 50 mL), dried (MgSO ₄ ), filtered and concentrated. The compound crude was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (70 mg, 31%).

Example 108

2-Cyclopentyl- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (8), 6,9,11-tetraen-3-yl] acetamide (ABR 239558)

To a stirred solution of 2-cyclopentylacetamide (350 mg, 2.75 mmol) in DMF (20 mL) was added pyridine (102 L, 1.27 mmol) followed by methyl 3,3,3-trifluoro- Oxopropanoate (395 mg, 2.53 mmol) was added at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. Further, pyridine (204 L, 2.54 mmol) and methyl 3,3,3-trifluoro-2-oxopropanoate (395 mg, 2.53 mmol) were added in portions over 3 days. Thionyl chloride (92 [mu] L, 1.27 mmol) was added at 0 [deg.] C and the reaction was stirred at 0 &lt; 0 &gt; C for 1 hour. Further thionyl chloride (92 [mu] L, 1.27 mmol) was added at 0 [deg.] C and the reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated, and the residue was eluted through a silica short pad with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (10 mL) under nitrogen. (355 mg, 2.20 mmol) and triethylamine (366 [mu] L, 2.75 mmol) were added and the reaction mixture was stirred at room temperature for 18 h Lt; / RTI &gt; The reaction mixture was then diluted with EtOAc (30 mL) and rinsed with water (4 x 50 mL) and brine (2 x 50 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 0-8% MeOH in DCM as eluent. Further purification by tritylation in DCM gave the title compound as a white solid (36 mg, 3%).

Example 109

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3,5-difluorobenzamide (ABR 239456)

N- [10,11- dichloro (trifluoromethyl) -4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca-1 (12), 6 , 8,10-tetraen-3-yl] oxane-4-carboxamide was used, but the following modifications were added. In the first reaction step, 2- (3,5-difluorophenyl) acetamide was used in place of oxacan-4-carboxamide to prepare the acylimine intermediate product. In the second reaction step, 5,6-dimethyl-1H-1,3-benzodiazole-2-amine was used in place of 5,6-dichloro-1H-1,3-benzodiazole- . The crude product was purified by silica chromatography using 3% MeOH in DCM as eluent. Further purification by trituration in DCM / MeOH followed by pentane afforded the title compound (4%).

Example 110

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6-fluoropyridine-2- carboxamide (ABR 239784)

To a stirred solution of 6-fluoropyridine-2-carboxamide (1.51 g, 10.79 mmol) in DMF (5 mL) was added pyridine (870 L, 10.79 mmol) and methyl 3,3,3- Oxopropanoate (1.65 mL, 16.19 mmol) was added under nitrogen. The reaction was stirred at room temperature for 16 hours. Thionyl chloride (790 [mu] L, 10.79 mmol) was added dropwise at 0 [deg.] C. The reaction mixture was stirred for a further 2 h and then concentrated. The residue was eluted through a silica shortpot with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (5 mL) under nitrogen. Acyl intermediate was added to 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (1.45 g, 8.99 mmol) in DMF (10 ml) followed by the addition of triethylamine mL, 10.79 mmol). The reaction mixture was stirred for an additional 16 hours and then concentrated. The residue was dissolved in EtOAc (150 mL), was water (2 x 100 mL), then dried, rinse with 10% citric acid _{(aq) (50 mL)} and Dublin (100 mL) (MgSO _4), filtered, and concentrated . The crude product was purified by tritylation in DCM to give the title compound as a white solid (2.35 g, 61%).

Example 111

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 (8), 6,9,11-tetraen-3-yl] -6- [(2-methoxyethyl) amino] pyridine- 2- carboxamide (ABR 239496)

To a solution of N- [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -dodeca -2-carboxamide (300 mg, 0.85 mmol) in anhydrous tetrahydrofuran (10 mL) was added K ₂ CO ₃ (235 mg, 1.70 mmol) and 2-methoxyethan-l-amine (128 mg, 1.70 mmol). The reaction mixture was heated at 90 &lt; 0 &gt; C for 4 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were rinsed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method B) to give the title compound as a white solid (60 mg, 15%).

Example 112

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2-phenylacetamide (ABR 239500)

To a stirred solution of 2-phenylacetamide (1.20 g, 8.88 mmol) in DMF (15 mL) was added pyridine (755 μL, 8.88 mmol) followed by ethyl 3,3,3-trifluoro- (1.51 g, 8.88 mmol) was added at room temperature under argon. The reaction mixture was stirred at room temperature for 1 hour. Thionyl chloride (644 [mu] L, 8.88 mmol). The reaction was stirred at room temperature for a further 16 h and then concentrated. The remaining acyl intermediate was dissolved in DMF (5 mL) under argon. Amine (1.07 g, 6.66 mmol) and triethylamine (1.62 mL, 11.54 mmol) were added and the reaction mixture was stirred at room temperature for 4 hours Respectively. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were rinsed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica chromatography using 3% MeOH in DCM as eluent to give the title compound as a white solid (225 mg, 3%).

Example 113 Synthesis of

2- (3,5-Dichlorophenyl) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] acetamide (ABR 239503)

N- [10,11- dichloro (trifluoromethyl) -4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca-1 (12), 6 , 8,10-tetraen-3-yl] oxane-4-carboxamide was used, but the following modifications were added. In the first reaction step, 2- (3,5-dichlorophenyl) acetamide was used in place of oxacan-4-carboxamide to prepare the acylimine intermediate product. In the second reaction step, 5,6-dimethyl-1H-1,3-benzodiazole-2-amine was used in place of 5,6-dichloro-1H-1,3-benzodiazole- . The crude product was purified by silica chromatography using 3% MeOH in DCM as eluent to give the title compound as a white solid (4%).

Example 114

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (3,4,5-trimethoxyphenyl) propanamide (ABR 239529)

N- [10,11- dichloro (trifluoromethyl) -4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca-1 (12), 6 , 8,10-tetraen-3-yl] oxane-4-carboxamide was used, but the following modifications were added. In the first reaction step, 3- (3,4,5-trimethoxyphenyl) propanamide was used in place of oxacan-4-carboxamide to prepare the acylimine intermediate product. In the second reaction step, 5,6-dimethyl-1H-1,3-benzodiazole-2-amine was used in place of 5,6-dichloro-1H-1,3-benzodiazole- . The crude product was purified by silica chromatography using 3% MeOH in DCM as eluent to give the title compound as a white solid (10%).

Example 115

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3- methanesulfonylbenzamide (ABR 239489)

To a stirred solution of 3-methanesulfonylbenzamide (800 mg, 4.02 mmol) in DMF (10 mL) was added pyridine (342 μL, 4.02 mmol) followed by ethyl 3,3,3-trifluoro- Oxopropanoate (532 [mu] L, 4.02 mmol) was added at room temperature under argon. The reaction mixture was stirred at room temperature for 1 hour and then thionyl chloride (292 [mu] L, 4.02 mmol) was added at 0 [deg.] C. The reaction was stirred at room temperature for a further 18 hours and then concentrated. The remaining acyl intermediate was added to DMF (10 mL) under argon. (485 mg, 3.01 mmol) and triethylamine (562 [mu] L, 4.02 mmol) were added and the reaction mixture was stirred at room temperature for 16 h Lt; / RTI &gt; The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were rinsed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica chromatography using 3% MeOH in DCM as eluent. Further purification by automated reverse phase HPLC (low pH method B) yielded the title compound as a white solid (20 mg, 0.5%).

Example 116

3-Bromo-N- [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] benzamide (ABR 239785)

Methyl 3,3,3-trifluoro-2-oxopropanoate (395 L, 3.88 mmol) was added to a stirred solution of 3-bromobenzamide (777 mg, 3.88 mmol) in DMF (7 mL) Then pyridine (313 [mu] L, 3.88 mmol) was added at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. Thionyl chloride (282 [mu] L, 3.88 mmol) was added at 0 [deg.] C and then the reaction mixture was stirred at 0 &lt; 0 &gt; C for 1 hour. The reaction mixture was concentrated, and the residue was eluted through a silica short pad with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (7 mL) under nitrogen. A solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (98 mg, 0.57 mmol) in DMF (7 mL) and triethylamine (619 μL, 4.65 mmol) The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (80 mL) and water (40 mL). The precipitate was filtered off and stored. The organic phase was rinsed with water (3 x 40 mL) and brine (40 mL). The organic phase was then dried (Na ₂ SO ₄ ), filtered, concentrated and thentreated with EtOAc. The resulting solid was combined with the previous precipitate and dissolved in EtOAc (10 mL) and rinsed with 10% citric acid _(aq) (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound as a white solid (120 mg, 8%).

Example 117

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3 - [(2- methoxyethyl) amino] benzamide (ABR 239638)

A microwave tube, a 3-bromo--N- [10,11- dimethyl-4-oxo-3- (trifluoro-methyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^{2, 6} ] dodeca-1 (8), 6,9,11-tetraen-3-yl] benzamide A (300 mg, 0.64 mmol), CuI (24 mg, 0.13 mmol), L- proline (30 mg, 0.26 mmol) and _{K 3 PO 4 (273 mg,} 1.28 mmol) was charged. Degassed DMSO (9 mL) and 2-methoxyethan-l-amine (193 mg, 2.57 mmol) were added. The reaction mixture was heated in a microwave at 80 &lt; 0 &gt; C for 2 h, then diluted with EtOAc (100 mL) and water (80 mL). The organic layer was rinsed with 2M aqueous ammonia solution (80 mL), water (80 mL) and brine (80 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a gray solid (60 mg, 20%).

Example 118

2-Bromo-N- [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -1,3-thiazole-4- carboxamide (ABR 239786)

Bromo-1,3-thiazole-4-carboxamide (456 mg, 2.20 mmol) in DMF (5 mL) was added methyl 3,3,3-trifluoro- (431 [mu] L, 4.23 mmol) and pyridine (178 [mu] L, 2.20 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. Thionyl bromide (171 [mu] L, 2.20 mmol) was added at 0 [deg.] C and then the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was eluted through a silica short pad with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (10 mL) under nitrogen. A solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (284 mg, 1.76 mmol) in DMF (10 mL) and triethylamine (352 μL, 2.64 mmol) The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated. The residue was diluted with EtOAc (50 mL) and rinsed with 10% citric acid _(aq) (15 mL), water (2 x 20 mL) and brine (20 mL). The organic phase was dried (Na ₂ SO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 5-20% MeOH in DCM as eluent to afford the title compound as a white solid (200 mg, 24%).

Example 119

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2 - [(2- methoxyethyl) amino] -1,3-thiazole- 239655)

DMF (trifluoromethyl) 2-Bromo -N- [10,11- dimethyl-4-oxo-3- (4 mL) -2,5,7- triaza-tricyclo - [6.4.0.0 ^{2 , 6} ] dodeca-1 (8), 6,9,11-tetraen-3-yl] -1,3-thiazole-4-carboxamide (263 mg, 0.55 mmol) , K ₂ CO ₃ (153 mg, 1.11 mmol) and 2-methoxyethan-1 -amine (96 μL, 1.11 mmol) were added. The reaction mixture was heated at 90 &lt; 0 &gt; C for 24 h and then concentrated. The residue was diluted with water and titrated to pH 6 by addition of 10% citric acid _(aq) . The aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic extracts were rinsed with water (2 x 15 mL) and brine (15 mL). The organic phase was dried (Na ₂ SO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (45 mg, 17%).

Example 120

N- [9-Bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239508)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- ), 2,7,14-tetraen-11-yl] propanamide was used instead of 4-bromo-1H-1,3-benzodiazole- - indeno [5,6-d] imidazol-2-amine. The crude product was purified by filtration in DCM to give the title compound (17%).

Example 121

N- [9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239436)

To a microwave tube was added N- [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] (150 mg, 0.33 mmol), Zn (CN) ₂ (58 mg, 0.49 mmol), Pd (dppf) Cl ₂ (40 mg, 0.05 mmol) and degassed DMF (3 mL). The reaction mixture was heated in a microwave for 10 minutes at 180 &lt; 0 &gt; C. The reaction mixture was reprocessed with Zn (CN) ₂ (58 mg, 0.49 mmol) and Pd (dppf) Cl ₂ (40 mg, 0.05 mmol) and further heated in a microwave at 180 ° C for 10 min. The reaction was filtered. The filtrate was diluted with EtOAc (15 mL) and rinsed with water (5 x 10 mL). The organic phase was dried (Na ₂ SO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 40% EtOAc in heptane as eluent to give the title compound as a white solid (18 mg, 14%).

Example 122

N- [9-acetyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239448)

To a microwave tube was added N- [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] 3-yl] -3-cyclopentylpropanamide (100 mg, 0.22 mmol), palladium (II) acetate (1.4 mg, 0.006 mmol), propane- die one bis (diphenyl phosphate) (5.7 mg, 0.014 mmol) , K 2 CO 3 (36 mg, 0.26 mmol), 1- ( ethenyl the oxy) butane (142 ㎕, 1.09 mmol) and degassed DMF / water ( 4: 1, 1 ml) was charged under nitrogen. The reaction was heated in a microwave at 100 &lt; 0 &gt; C for 1 hour. The reaction was diluted with EtOAc (17 mL) and rinsed with water (4 x 5 mL) and brine (6 mL). The organic phase was dried (Na ₂ SO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (56 mg, 61%).

Example 123

N- [10-Chloro-9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239521)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- 2-amino-5-chloro-1H-1,3-benzodiazole-4-carbonitrile was synthesized according to the method of 1H, 5H , 6H, 7H-indeno [5,6-d] imidazol-2-amine. After the addition of the thionyl chloride, the reaction was stirred at 0 ° C for 1 hour and concentrated. A solid was precipitated with a water-based work-up and collected by filtration to give the title compound (36%).

Example 124

3-Cyclopentyl- N- [9-fluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239535)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- ), 2,7,14-tetraen-11-yl] propanamide was used instead of 4-fluoro-1H-1,3-benzodiazole- - indeno [5,6-d] imidazol-2-amine. After the addition of the thionyl chloride, the reaction was stirred at 0 ° C for 1 hour and concentrated. The crude product was purified by trituration in DCM to give the title compound (19%).

Example 125

3-Cyclopentyl- N- [9,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239545)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- ), 2,7,14-tetraen-11-yl] propanamide was used but 4,6-dimethyl-1H-1,3-benzodiazole- , 7H-indeno [5,6-d] imidazol-2-amine. An additional equivalent of thionyl chloride was added at 0 &lt; 0 &gt; C 1 h after the first addition, then the reaction was stirred at 0 &lt; 0 &gt; C for an additional 1 h and concentrated. The crude product was purified by trituration in a minimum amount of DCM to give the title compound (26%).

Example 126

N- [9-Chloro-10-fluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239559)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- ), 2,7,14-tetraen-11-yl] propanamide was used but the 4-chloro-5-fluoro-1H-1,3-benzodiazole- , 6H, 7H-indeno [5,6-d] imidazol-2-amine. After the addition of the thionyl chloride, the reaction was stirred at 0 ° C for 1 hour and concentrated. The crude product was purified by filtration in DCM to give the title compound as a white solid (16%).

Example 127

N- [10-Chloro-9-methyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239569)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- Methyl-1H-1,3-benzodiazole-2-amine was synthesized in the same manner as 1H, 5H, 6H, 7H-indeno [5,6-d] imidazol-2-amine. An additional equivalent of thionyl chloride was added at 0 &lt; 0 &gt; C 1 h after the first addition, then the reaction was stirred at 0 &lt; 0 &gt; C for an additional 1 h and concentrated. The crude product was purified by tritylation in DCM to give the title compound (35%).

Example 128

3-Cyclopentyl- N- [4-oxo-3,9-bis (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] propanamide (ABR 239544)

To a stirred solution of 3-cyclopentylpropanamide (200 mg, 1.42 mmol) in DMF (20 mL) was added methyl 3,3,3-trifluoro-2-oxopropanoate (442 mg, 2.83 mmol) Pyridine (114 [mu] L, 1.42 mmol) was added at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. Thionyl chloride (103 [mu] L, 1.42 mmol) was added at 0 [deg.] C and then the reaction mixture was stirred at 0 &lt; 0 &gt; C for 1 hour. The reaction mixture was concentrated, and the residue was eluted through a silica short pad with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (15 mL) under nitrogen. Amine (228 mg, 1.13 mmol) and triethylamine (188 [mu] L, 1.42 mmol) were added and the reaction mixture was stirred at room temperature for 2 Lt; / RTI &gt; The reaction mixture was concentrated. The residue was diluted with EtOAc (100 mL) and rinsed with water (3 x 100 mL) and brine (3 x 100 mL). The organic phase was dried (MgSO _4), filtered and concentrated. The crude product was triturated in DCM and the title compound was obtained as a white solid (194 mg, 31).

Example 129

N- [11-Bromo-4-oxo-3,9-bis (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239577)

A 3-cyclopentyl stirred in DCM (5 mL) - N- [ ( trifluoromethyl) 4-oxo-3,9-bis -2,5,7- triaza-tricyclo - [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] propanamide (50 mg, 0.11 mmol) in dichloromethane was added NBS (30 mg, 0.17 mmol). The prepared suspension was stirred at room temperature for 48 hours. Additional NBS (60 mg, 0.34 mmol) and DCM (25 mL) were added over 8 days. The reaction mixture was then diluted with DCM (50 mL) and rinsed with water (3 x 25 mL) and saturated NaHCO _{3 (aq)} (25 mL). The organic phase was dried (MgSO _4), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (14 mg, 24%).

Example 130

N- [10-Chloro-9-fluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239603)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- Chloro-4-fluoro-1H-1, 3-benzodiazole-2-amine was obtained in the same manner as 1H, 5H , 6H, 7H-indeno [5,6-d] imidazol-2-amine. After the addition of the thionyl chloride, the reaction was stirred at 0 ° C for 1 hour and concentrated. The crude product was purified by trituration in DCM to give the title compound (3%).

Example 131

3-Cyclopentyl- N- [9-fluoro-10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239551)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- Fluoro-5-methoxy-1H-1,3-benzodiazole-2-amine was obtained in the same manner as 1H, 5H, 6H, 7H-indeno [5,6-d] imidazol-2-amine. After the addition of the thionyl chloride, the reaction was stirred at 0 ° C for 1 hour and concentrated. The final step was carried out within 2 hours after addition of 4-fluoro-5-methoxy-1H-1,3-benzodiazole-2-amine. The crude product was purified by trituration in DCM to give the title compound (10%).

Example 132

3-Cyclopentyl- N- [9- (methylsulfanyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239636)

3-cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo [7.6.0.0 ^3,7 .0 ^10,14 ] pentadeca- ), 2,7,14-tetraen-11-yl] propanamide was used, but 4- (methylsulfanyl) -1H-1,3-benzodiazole- 6H, 7H-indeno [5,6-d] imidazol-2-amine. After the addition of the thionyl chloride, the reaction was stirred at 0 ° C for 1 hour and concentrated. The crude product was purified by silica chromatography using 1-8% MeOH in DCM as eluent to give the title compound as a pale brown oil (quantitative yield).

Example 133

3-Cyclopentyl- N- [9-methanesulfonyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239639)

To a stirred solution of 3-cyclopentyl- N- [9- (methylsulfanyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4. 0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] propanamide (100 mg, 0.23 mmol) solution, OXONE (359 mg, 0.59 mmol) aqueous solution (2 mL ) At 0 &lt; 0 &gt; C. After stirring for 4 h, the reaction was diluted with EtOAc (30 mL) and washed sequentially with water (2 x 10 mL) and brine (10 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated to give the title product as a pale brown solid (100 mg, 93%).

Example 134

N- [9-Bromo-10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239730)

To a solution of 3-cyclopentyl- N- [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (300 mg, 0.71 mmol). The resulting suspension was stirred at room temperature for 18 hours. Additional NBS (165 mg, 0.93 mmol) was added. The reaction was stirred for a further 4 h and then concentrated. The residue was dissolved in EtOAc (100 mL) and rinsed with water (2 x 50 mL), saturated citric acid _(aq) (50 mL) and brine (50 mL). The organic phase was dried (MgSO _4), filtered and concentrated. The crude product was purified by filtration in DCM to give the title compound as a white solid (160 mg, 46%).

Example 135

N- [9,10-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6-fluoropyridine- 2- carboxamide (ABR 239538)

To a stirred solution of 6-fluoropyridine-2-carboxamide (140 mg, 1.00 mmol) in DMF (10 mL) was added methyl 3,3,3-trifluoro-2-oxopropanoate (312 mg, 2.00 mmol) followed by pyridine (81 [mu] L, 1.00 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. Thionyl chloride (87 L, 1.20 mmol) was added at 0 &lt; 0 &gt; C and then the reaction mixture was stirred at 0 &lt; 0 &gt; C for 1 hour. The reaction mixture was concentrated, and the residue was eluted through a silica short pad with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (10 mL) under nitrogen. 1,3-benzodiazole-2-amine (151 mg, 0.75 mmol) and triethylamine (133 L, 1.00 mmol) were added. The reaction mixture was stirred at room temperature for a further 2 hours and then concentrated. The residue was dissolved in EtOAc (100 mL) and rinsed with water (3 x 50 mL) and brine (3 x 50 mL). The organic phase was dried (MgSO _4), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (122 mg, 27%).

Example 136

N- [9,10-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 (8), 6,9,11-tetraen-3-yl] -6- [(2-methoxyethyl) amino] pyridine- 2- carboxamide (ABR 239542)

To a solution of N- [9,10-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -dodeca (80 mg, 0.18 mmol) in anhydrous tetrahydrofuran (2 mL) was added K ₂ CO ₃ (62 mg, 0.45 mmol) and 2-methoxyethan-l-amine (27 mg, 0.36 mmol). The reaction mixture was heated at 100 &lt; 0 &gt; C for 12 h. Amine (27 mg, 0.36 mmol) and K ₂ CO ₃ (62 mg, 0.45 mmol) were further added. The reaction was further heated at 100 &lt; 0 &gt; C for 6 h and then concentrated. The residue was dissolved in EtOAc (50 mL) and rinsed sequentially with water (3 x 25 mL) and brine (2 x 25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The compound crude was purified by automated reverse phase HPLC (high pH) to give the title compound as a white solid (20 mg, 22%).

Example 137

N- [10-Chloro-9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6-fluoropyridine-2- carboxamide (ABR 239579)

To a stirred solution of 6-fluoropyridine-2-carboxamide (175 mg, 1.25 mmol) in DMF (10 mL) was added methyl 3,3,3-trifluoro-2-oxopropanoate (390 mg, 2.49 mmol) followed by pyridine (100 [mu] L, 1.52 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. Thionyl chloride (91 [mu] L, 1.25 mmol) was added at 0 [deg.] C and then the reaction mixture was stirred at 0 &lt; 0 &gt; C for 1 hour. The reaction mixture was concentrated, and the residue was eluted with DCM through a silica short pad and filtered under an inert atmosphere. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (10 mL) under an inert atmosphere. A solution of 2-amino-5-chloro-lH-l, 3-benzodiazole-4-carbonitrile (200 mg, 1.04 mmol) in DMF (2 mL) and triethylamine (133 L, 1.00 mmol) , And the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated. The residue was dissolved in EtOAc (50 mL) and rinsed with water (3 x 50 mL) and brine (3 x 50 mL). The organic phase was dried (MgSO _4), filtered and concentrated. The crude product was purified by silica chromatography using 0-10% MeOH in DCM as eluent. Additional purification (low pH method) was performed using automated reversed phase HPLC to yield the title compound as a brown solid (115 mg, 25%).

Example 138

N- [10-Chloro-9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6 - [(2- methoxyethyl) amino] pyridine- 2- carboxamide (ABR 239585)

DMF (2 mL) of N- [10- chloro-9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca Carboxamide (75 mg, 0.17 mmol) in a sealed tube was added K ₂ CO (8 mg, 0.12 mmol) in a sealed tube, to a solution of 6-fluoro- ₃ (71 mg, 0.51 mmol) and 2-methoxyethan-1 -amine (39 mg, 0.51 mmol). First, the reaction mixture was heated at 100 DEG C for 2 hours. The reaction was then heated for a further 20 hours. During this period, additional 2-methoxyethan-1 -amine (80 mg, 1.02 mmol) was added in portions during the reaction while reacting at room temperature. The reaction mixture was then concentrated. The residue was dissolved in EtOAc (100 mL) and rinsed sequentially with water (3 x 50 mL) and brine (3 x 50 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The compound was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (22 mg, 26%).

Example 139

N- [10-Chloro-9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2 - [(2- methoxyethyl) amino] -1,3-thiazole- 239624)

To a stirred solution of 2-bromo-1,3-thiazole-4-carboxamide (194 mg, 0.93 mmol) in DMF (10 mL) was added methyl 3,3,3-trifluoro- (291 mg, 1.86 mmol) was added followed by pyridine (75 L, 0.93 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. Thionyl chloride (68 [mu] L, 0.93 mmol) was added dropwise at 0 &lt; 0 &gt; C. The solution was stirred at 0 &lt; 0 &gt; C for an additional 1 h and then concentrated. The residue was eluted through a silica short pad with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (10 mL) under nitrogen. A solution of 2-amino-5-chloro-lH-l, 3-benzodiazole-4-carbonitrile (150 mg, 0.78 mmol) in DMF (5 mL) and triethylamine (124 L, 0.935 mmol) , And the reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated and the residue was dissolved in EtOAc (50 mL) and then rinsed sequentially with 10% citric acid _(aq) (25 mL), water (2 x 25 mL) and brine (2 x 25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 2-6% MeOH in DCM as eluent to give 2-bromo- N- [10-chloro-9-cyano- Methyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (8), 6,9,11-tetraen- 4-carboxamide and 2-chloro - N- [10- chloro-9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^{2 , 6} ] dodeca-1 (8), 6,9,11-tetraen-3-yl] -1,3-thiazole-4- carboxamide.

A microwave tube, 2-bromo - N- [10- chloro-9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^{2 , 6} ] dodeca-1 (8), 6,9,11-tetraen-3-yl] -1,3- thiazole- 4- carboxamide and 2-chloro- N- -Cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (8), 6,9,11-tetra (70 mg), K ₂ CO ₃ (57 mg, 0.42 mmol), 2-methoxyethan-1 -amine (36 mg, Mu] l, 0.42 mmol) and dioxane (2 mL). The reaction was heated in a microwave at 130 &lt; 0 &gt; C for 1 hour. Adding 2-methoxy-ethane-1-amine (36 ㎕, 0.42 mmol) and _{K 2 CO 3 (57 mg,} 0.42 mmol) was added. The reaction was heated for an additional hour and then concentrated. The residue was dissolved in EtOAc (25 mL) and rinsed with water (25 mL), 10% citric acid _(aq) (25 mL) and brine (25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (3 mg).

Example 140

Diastereomeric mixture. N- [10-Chloro-9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triaza- tricyclo [ ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6 - {[(2S) -1- methoxypropan- Mid (ABR 239586)

DMF (2 mL) of N- [10- chloro-9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca Carboxamide (75 mg, 0.55 mmol) in a sealed tube, to a solution of K ₂ CO (8), 6,9,11-tetraen-3-yl] -6-fluoropyridine- ₃ (185 mg, 1.34 mmol) and (2S) -1-methoxypropan-2-amine (49 mg, 0.55 mmol). First, the reaction mixture was heated at 100 DEG C for 6 hours. The reaction was then heated for a further 22 hours. During this period, additional K ₂ CO ₃ (150 mg, 1.10 mmol) and (2S) -1-methoxypropan-2-amine (98 mg, 1.10 mmol) were added in portions during the reaction at room temperature during the reprocessing. The reaction mixture was then concentrated. The residue was dissolved in EtOAc (50 mL) and rinsed with water (3 x 25 mL) and then brine (3 x 25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The compound was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a yellow solid (14 mg, 15%) as a mixture of diastereomers.

Example 141

N- [9, 10-Difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6-fluoropyridine-2-carboxamide (ABR 239787)

To a stirred solution of 6-fluoropyridine-2-carboxamide (190 mg, 1.36 mmol) in DMF (2 mL) was added methyl 3,3,3-trifluoro-2-oxopropanoate mmol) was added followed by pyridine (109 [mu] L, 1.36 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. Thionyl chloride (99 [mu] L, 1.36 mmol) was added at 0 [deg.] C and then the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated, and the residue was eluted with DCM through a silica short pad under an inert atmosphere. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (5 mL) under nitrogen. A solution of 4,5-difluoro-lH-l, 3-benzodiazole-2-amine (153 mg, 0.90 mmol) in DMF (4 mL) and triethylamine (181 L, 1.36 mmol) The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (30 mL) and rinsed with water (4 x 20 mL) and brine (20 mL). The organic phase was dried (Na ₂ SO _4), filtered, and concentrated. The crude product was purified by filtration in DCM to give the title compound as a white solid (123 mg, 33%).

Example 142 [

N- [9, 10-Difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 (8), 6,9,11-tetraen-3-yl] -6- [(2-methoxyethyl) amino] pyridine- 2- carboxamide (ABR 239632)

To a solution of N- [9,10-difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca -2-carboxamide (123 mg, 0.30 mmol) in anhydrous tetrahydrofuran (2 ml) was added K ₂ CO ₃ (102 mg, 0.74 mmol) and 2-methoxyethan-l-amine (45 mg, 0.59 mmol). The reaction mixture was heated at 100 &lt; 0 &gt; C for 18 hours. The reaction was diluted with EtOAc (50 mL) and rinsed with water (3 x 25 mL) and then brine (3 x 25 mL). The organic phase was dried (Na ₂ SO _4), filtered, and concentrated. The compound crude was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (36 mg, 26%).

Example 143

Diastereomer 1: (2S) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2-phenylpropanamide (ABR 239609)

Example 144

Diastereomer 2: (2S) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2-phenylpropanamide (ABR 239621)

To the stirred solution of (2S) -2-phenylpropanamide (222 mg, 1.49 mmol) in DMF (10 mL) was added pyridine (120 L, 1.49 mmol) followed by methyl 3,3,3- 2-oxopropanoate (465 mg, 2.98 mmol) was added at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. Thionyl chloride (108 [mu] L, 1.49 mmol) was added at 0 [deg.] C, then the reaction mixture was stirred for 1 h at 0 [deg.] C. The reaction mixture was then concentrated and the residue was filtered through a silica short pad with DCM eluting with nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (5 mL) under nitrogen. A solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (200 mg, 1.24 mmol) in DMF (5 mL) and triethylamine (198 L, 1.49 mmol) The mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated. The residue was diluted with EtOAc (50 mL) and rinsed with water (2 x 25 mL), 10% citric acid _(aq) (2 x 25 mL) and brine (2 x 25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by trituration in DCM to give a clear diastereomeric mixture. This was recrystallized in EtOAc / heptane to give the diastereoisomer 1 as a white solid (95 mg, 18%) as a single diastereomer with undetermined stereochemistry at the quarter center. The mother liquor was concentrated and purified by automated reverse phase HPLC (low pH method A) to give the diastereoisomer 2 as a single diastereomer with a pendant stereochemistry at the quarter center as a white solid ( 33 mg, 6%).

Example 145

Diastereomeric mixture. (2S) -3-cyclopentyl- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2-methylpropanamide (ABR 239666)

(a) diastereoisomer 1: (2S) -3-cyclopentyl- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2-methylpropanamide (ABR 239667)

(b) diastereoisomer 2: (2S) -3-Cyclopentyl- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2-methylpropanamide (ABR 239668)

Pyridine (132 L, 1.64 mmol) was added to a stirred solution of (2S) -3-cyclopentyl-2-methylpropanamide (254 mg, 1.64 mmol) in DMF (15 mL) -Trifluoro-2-oxopropanoate (511 mg, 3.28 mmol) was added at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. Thionyl chloride (118 [mu] L, 1.64 mmol) was added at 0 [deg.] C and the reaction was stirred at 0 [deg.] C for 1 hour. The reaction mixture was then concentrated and the residue was filtered through a silica short pad eluting with DCM and under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (10 mL) under nitrogen. A solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (220 mg, 1.36 mmol) in DMF (10 mL) and triethylamine (229 L, 1.64 mmol) The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was diluted with EtOAc (50 mL) and rinsed with water (3 x 50 mL) and then brine (3 x 50 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by tritylation in DCM to give the title compound as a yellow solid as a clear mixture of diastereomers. The residue was purified by SFC using CO ₂ and MeOH with 0.1% formic acid as the mobile phase and Chiralpak AD-H column as diastereomeric mixture (61 mg, 11%) to give the diastereomer 1 as a quarter (26 mg, 5%) as a single diastereomer with a pendant stereochemistry at the center of the molecule, and diastereoisomer 2 as a single diastereomer with undetermined stereochemistry at the quarter center Obtained as a solid (40 mg, 7%).

Example 146

(a) diastereomer 1: (2S) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2-hydroxy-2-phenylacetamide (ABR 239664)

(b) diastereomer 2: (2S) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2-hydroxy-2-phenylacetamide (ABR 239665)

To a stirred solution of (S) - {[10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2, (Aq ₎ (597 [mu] l, 0.15 mmol) was added to a solution of 4-amino- ^6- dodeca-l (8), 6,9,11-tetraen- 1.20 mmol). The reaction mixture was heated at 40 &lt; 0 &gt; C for 3 h and then concentrated. The residue was dissolved in EtOAc (50 mL) and rinsed with 10% citric acid _(aq) (2 x 30 mL) and then brine (2 x 30 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by reverse phase C18 chromatography using an acidic eluent to give a clear mixture of diastereoisomers. Separation of the mixture of diastereoisomers by automated reversed phase HPLC (low pH method A) afforded diastereoisomer 1 as a white solid as a single diastereomer with undetermined stereochemistry at the quarter center (38 mg, 8%), the diastereoisomer 2 was obtained as a white solid (80 mg, 18%) as a single diastereomer with undetermined stereochemistry at the quarter center.

Example 147

(a) diastereomer 1: (2S) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2-methoxy- 2- phenylacetamide (ABR 239622)

(b) diastereomer 2: (2S) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2-methoxy- 2- phenylacetamide (ABR 239623)

Pyridine (90 L, 1.12 mmol) was added to a stirred solution of (2S) -2-methoxy-2-phenylacetamide (184 mg, 1.12 mmol) in DMF (10 mL) -Trifluoro-2-oxopropanoate (349 mg, 2.23 mmol) was added at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. Thionyl chloride (81 [mu] L, 1.12 mmol) was added at 0 [deg.] C and the reaction was stirred at 0 [deg.] C for 1 hour. The reaction mixture was concentrated and the residue was filtered through a silica short pad eluting with DCM and under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (10 mL) under nitrogen. A solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (150 mg, 0.93 mmol) in DMF (5 mL) and triethylamine (149 L, 1.12 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was diluted with EtOAc (50 mL) and rinsed with water (2 x 25 mL), 10% citric acid _(aq) (2 x 25 mL) and brine (2 x 25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by trituration in DCM to give a clear mixture of diastereoisomers. Separating the mixture of diastereomers in the automatic reverse phase HPLC (the low pH method A) and, to give the diastereomers 1 as a single diastereomer with the buckle of the three-dimensional chemical resistance to the quarter Nourishing center as a white solid which (50 mg, 12 %), Diastereomer 2 (27 mg, 7%) as a white solid as a single diastereomer with undetermined stereochemistry at the quarter center.

Example 148

Methyl 3- (3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxylate (ABR 239934)

Methyl 3,3,3-trifluoro-2-oxopropanoate (2.40 mL, 23.5 mmol) was added to a stirred solution of 3-cyclopentylpropanamide (2.22 g, 15.7 mmol) in anhydrous DCM , Then pyridine (1.27 mL, 15.7 mmol) was added under nitrogen. The reaction was stirred at room temperature for 2 hours. Thionyl chloride (1.14 mL, 15.69 mmol) was added at 0 &lt; 0 &gt; C. The reaction was stirred at 0 &lt; 0 &gt; C for 1 hour and then filtered through a silica short pad eluting with DCM and under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (25 mL) under nitrogen. Acyl intermediate was treated with methyl 2-amino-1H-1,3-benzodiazole-4-carboxylate (available via literature method: PCT international application 2008157270) in DMF (25 ml) 13.1 mmol) in tetrahydrofuran, and then triethylamine (5.22 mL, 39.2 mmol) was added. The reaction mixture was stirred for a further 18 hours and then concentrated. The residue was dissolved in EtOAc (100 mL) and rinsed with saturated citric acid _(aq) (30 mL). The phases were extracted with EtOAc (100 mL). Rinse the combined organic extracts were Dublin (2 x 15 mL) then dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 0-10% MeOH in DCM as eluent to afford the title compound as a green solid (990 mg, 17%).

Example 149

3-Cyclopentyl- N - [9-iodo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 240060)

Methyl 3,3,3-trifluoro-2-oxopropanoate (0.65 mL, 6.35 mmol) was added to a stirred solution of 3-cyclopentylpropanamide (748 mg, 5.29 mmol) in anhydrous DCM Then pyridine (0.43 mL, 5.29 mmol) was added under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. Thionyl chloride (0.38 mL, 5.29 mmol) was added at 0 &lt; 0 &gt; C. The reaction was stirred at 0 &lt; 0 &gt; C for 2 h, then filtered through a silica short pad eluting with DCM and under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (10 mL) under nitrogen. Acyl intermediate was added to a solution of 4-iodo-lH-l, 3-benzodiazole-2-amine (1.10 g, 4.23 mmol) in DMF (10 ml) followed by the addition of triethylamine (0.70 ml, 5.29 mmol). The reaction mixture was stirred for a further 4 h and then concentrated. The residue was dissolved in EtOAc (50 mL) and rinsed with 10% citric acid _(aq) (50 mL). The formed precipitate was filtered off. The phases were extracted with EtOAc (25 mL). Rinse the combined organic extracts were Dublin (2 x 50 mL) then dried (MgSO _4), filtered, and concentrated. The crude product was purified by tritylation in DCM to give the title compound as a white solid (798 mg, 27%).

Example 150

N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-methoxypyridine-3- carboxamide (ABR 240061)

To a stirred solution of 2-methoxypyridine-3-carboxamide (available under the method of PCT international application 2010101949) (300 mg, 1.97 mmol) in DMF (5 mL) was added methyl 3,3,3-tri Fluoro-2-oxopropanoate (0.24 mL, 2.37 mmol) was added followed by pyridine (0.16 mL, 1.97 mmol) under nitrogen. The reaction was stirred at room temperature for 16 hours. Thionyl chloride (0.14 mL, 1.97 mmol) was added at 0 &lt; 0 &gt; C. The reaction was stirred at 0 &lt; 0 &gt; C for 1 h and then concentrated. The residue was eluted through a silica shortpot with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (6 mL) under nitrogen. Acyl intermediate was added to a solution of 4-bromo-1H-1,3-benzodiazole-2-amine (334 mg, 1.58 mmol) in DMF (5 ml) followed by the addition of triethylamine , 1.97 mmol). The reaction mixture was stirred for a further 2 h and then concentrated. The residue was dissolved in EtOAc (30 mL) and rinsed with saturated citric acid _(aq) (15 mL). The phases were extracted with EtOAc (2 x 15 mL). Rinse the combined organic extracts with water (2 x 20 mL) and Dublin (2 x 20 mL), dried (MgSO _4), filtered, and concentrated. The crude product was purified by tritylation in DCM to give the title compound as a white solid (334 mg, 44%).

Example 151

N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-hydroxypyridine-3- carboxamide (ABR 240062)

To a stirred solution of N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca- To a suspension of 1 (12), 6,8,10-tetraen-3-yl] -2-methoxypyridine-3- carboxamide (334 mg, 0.7 mmol) Moboran / DCM (2.09 mL, 2.09 mmol) was added. The reaction was warmed to room temperature and stirred for 4 hours. The reaction was cooled to 0 C and an additional 1 M tribromoborane / DCM (2.09 mL, 2.09 mmol) was added. The reaction was warmed to room temperature and stirred for 4 hours. The reaction was quenched at 0 &lt; 0 &gt; C with water (15 mL). The precipitate formed was collected via filtration and then rinsed with water, DCM, EtOAc and water to give the title compound as a white solid (208 mg, 65%).

Example 152

(2S) - N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-cyclohexylpropanamide (ABR 240063)

To a solution of (2S) -2-cyclohexylpropanamide (280 mg, 1.64 mmol) in DMF (5 mL) under nitrogen was added methyl 3,3,3-trifluoro-2-oxopropanoate Mu] l, 2.46 mmol) followed by pyridine (132 [mu] L, 1.64 mmol). The reaction was stirred at room temperature for 1 hour. Thionyl chloride (119 [mu] L, 1.64 mmol) was added at 0 [deg.] C. The reaction was stirred at 0 &lt; 0 &gt; C for 1 h and then concentrated. The residue was eluted through a silica shortpot with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (4 mL) under nitrogen. Acyl intermediate was added to a solution of 4-bromo-1H-1,3-benzodiazole-2-amine (290 mg, 1.37 mmol) in DMF (2 mL) followed by the addition of triethylamine (204 [ 1.53 mmol). The reaction was stirred for 16 h and then concentrated. The residue was dissolved in EtOAc (15 mL) and rinsed with saturated citric acid _(aq) (15 mL). The phases were extracted with EtOAc (15 mL). Rinse the combined organic extracts were Dublin (2 x 15 mL), dried (MgSO _4), filtered, and concentrated. The crude product was purified by tritylation in DCM to give the title compound as a white solid (236 mg, 35%).

Example 153

(2S) -2- (Cyclopent-1-en-1-ylmethoxy) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 240068)

To a solution of amide (2S) -2- (cyclopent-1-en-l-ylmethoxy) propanamide (346 mg, 2.05 mmol) in anhydrous DCM (5 mL) was added pyridine (165 L, 2.05 mmol) Was added followed by methyl 3,3,3-trifluoro-2-oxopropanoate (639 mg, 4.09 mmol). The reaction was stirred at room temperature for 18 hours. Thionyl chloride (149 [mu] L, 2.05 mmol) was added at 0 [deg.] C. The reaction was stirred at 0 &lt; 0 &gt; C for 1 hour. The reaction was eluted through a silica shortpot with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (3 mL) under nitrogen. A solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (275 mg, 1.71 mmol) in DMF (2 mL) was added followed by triethylamine (286 μL, 2.05 mmol) . The reaction was stirred for 18 h and then concentrated. The residue was dissolved in EtOAc (30 mL) and rinsed with water (4 x 20 mL) and brine (20 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound as an orange solid (750 mg, quantitative yield).

Example 154

N - [11-chloro-9-iodo-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 240064)

Dioxane (4 mL) was stirred while a N - [9-bromo-11-chloro (trifluoromethyl) -4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (250 mg, 0.50 mmol) 1.5 mmol), copper (I) iodide (38 mg, 0.20 mmol) and N, N' -dimethylethane-l, 2-diamine (43 l, 0.4 mmol). First, the reaction was heated at 150 占 폚 for 2 hours. The temperature was then lowered to 120 DEG C for 2 hours and then lowered to 100 DEG C for the last 2 hours. The reaction was then concentrated and the residue was diluted with EtOAc (15 mL) and saturated citric acid _(aq) (25 mL). The phases were extracted with EtOAc (15 mL). The combined organic extract was obtained, rinse with water (15 mL) and Dublin (30 mL) and then dried (MgSO _4), filtered and concentrated to give the title compound as an orange solid (239 mg, 70%).

Example 155

N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] butanamide (ABR 240065)

Methyl 3,3,3-trifluoro-2-oxopropanoate (0.24 mL, 2.4 mmol) was added to a stirred solution of butanamide (205 mg, 2.36 mmol) in anhydrous DCM (6 mL) (0.18 mL, 2.3 mmol) was added under nitrogen. The reaction was stirred at room temperature for 1 hour. Thionyl chloride (0.16 mL, 2.3 mmol) was added at 0 &lt; 0 &gt; C. The reaction was stirred at 0 &lt; 0 &gt; C for 1 h, then filtered through a silica short pad eluting with DCM and under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (3 mL) under nitrogen. Acyl intermediate was added to a solution of 4-bromo-1H-1,3-benzodiazole-2-amine (400 mg, 1.89 mmol) in DMF (5 ml) followed by the addition of triethylamine , 2.3 mmol). The reaction mixture was stirred for an additional hour and then concentrated. The residue was diluted with EtOAc (60 mL) and 1M HCl _(aq) (40 mL). Dried rinse the organic phase with water (2 x 20 mL) and Dublin _{(20 mL) (Na 2 SO} 4) , filtered, and concentrated. The crude product was purified by silica chromatography using 0-15% MeOH in DCM as eluent to give the title compound as a yellow oil (650 mg, 76%).

Example 156

N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2- (cyclopentylamino) -1,3- thiazole- 4- carboxamide (ABR 240066)

To a stirred solution of 2-bromo-1,3-thiazole-4-carboxamide (2.93 g, 14.2 mmol) in DMF (80 mL) was added methyl 3,3,3-trifluoro- (4.42 g, 28.3 mmol) was added followed by pyridine (1.14 mL, 14.2 mmol) under nitrogen. The reaction was stirred at room temperature for 16 hours. Additional methyl 3,3,3-trifluoro-2-oxopropanoate (4.42 g, 28.3 mmol) was added and the reaction stirred for a further 4 h. Thionyl chloride (1.03 mL, 14.2 mmol) was added at 0 &lt; 0 &gt; C. The reaction was stirred at 0 &lt; 0 &gt; C for a further 2 h and then concentrated. The residue was eluted through a silica shortpot with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (10 mL) under nitrogen. Acyl intermediate was added to a solution of 4-bromo-1H-1,3-benzodiazol-2-amine (2.50 g, 11.8 mmol) in DMF (40 ml) followed by the addition of triethylamine (1.88 mL, 14.2 mmol). The reaction mixture was stirred for a further 2 h and then concentrated. The residue was dissolved in EtOAc (200 mL), and then dried, rinse with 10% citric acid _(aq) (2 x 100 mL), water (2 x 100 mL) and Dublin (2 x 100 mL) (MgSO _4), filtered And concentrated. The crude product was purified by trituration in DCM to give 2-bromo- N- [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [ 6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10-tetraen-3-yl] -1,3- thiazole- 4- carboxamide and N- [9- (12), 6,8,10-tetraen-3- (4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Chloro-l, 3-thiazole-4-carboxamide (3.70 g).

To a sealed tube was added 2-bromo- N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Carboxamide with N - [9-bromo-4-oxo-3- (tri (4-hydroxyphenyl) fluoromethyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] -2-chloro-l (500 mg), cyclopentanamine (0.39 mL, 4.0 mmol), K ₂ CO ₃ (546 mg, 3.95 mmol) and dioxane (5 mL) were charged . The tube was flushed with nitrogen, sealed, and then stirred at 130 DEG C for 20 hours. Cyclopentanamine (0.16 mL, 1.6 mmol) and K ₂ CO ₃ (219 mg, 1.58 mmol) were further added and the reaction was stirred at 130 ° C for 4 hours and at 120 ° C for 16 hours. The reaction mixture was then concentrated and the resulting residue was diluted with EtOAc (30 mL) and water (30 mL). The phases were extracted with EtOAc (30 mL). The combined organic extracts were rinsed with water (2 x 25 mL) and brine (50 mL) then dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by reverse phase C18 chromatography using an acidic eluent to give the title compound as an orange solid (150 mg, 33%).

Example 157

3-Cyclopentyl- N - [9-Iodo-10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 240067)

To a sealed tube was added N - [9-bromo-10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] 3-yl] -3-cyclopentylpropanamide (405 mg, 0.83 mmol), potassium iodide (412 mg, 2.48 mmol), copper (I ) Iodide (63 mg, 0.33 mmol), N, N' -dimethylethane-l, 2-diamine (71 L, 0.66 mmol) and dry dioxane (4 mL). The tube was flushed with nitrogen, sealed, and then stirred at 120 占 폚 for 16 hours and at 100 占 폚 for 4 hours. The reaction mixture was then concentrated. The resulting residue was diluted with EtOAc (20 mL) and saturated citric acid _(aq) (20 mL). The phases were extracted with EtOAc (15 mL). The combined organic extracts were rinsed with water (2 x 15 mL), dried (MgSO ₄ ), filtered and concentrated to give the title compound as a green solid (350 mg, 51%).

Example 158

3-Cyclopentyl- N - [9- (hydroxymethyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239922)

To a stirred solution of methyl 3- (3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^{2 , 6} ] dodeca-1 (12), 6,8,10-tetraene-9-carboxylate (480 mg, 1.09 mmol) in tetrahydrofuran (4.38 mL, 4.38 mmol). The reaction was allowed to warm to room temperature over 2 hours. The reaction mixture was then diluted with diethyl ether (20 mL). Water was added slowly at 0 &lt; 0 &gt; C and then 15% NaOH _(aq) was added. The reaction mixture was stirred for 1 hour. The precipitate was collected via filtration and then dissolved in EtOAc (30 mL) and acidified to pH 2 using 2M HCl _(aq) . Rinse the organic phase with Dublin (10 mL) dried (MgSO _4), filtered, and concentrated. The crude product was purified by filtration in DCM to give the title compound as a yellow solid (180 mg, 40%).

Example 159

N - [9-butyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239938)

To a solution of N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca- 3-yl] -3-cyclopentylpropanamide (300 mg, 0.65 mmol) and 2-methylprop-1-en-1-yl acetate (149 mg, (Tri-o-tolylphosphine) palladium (II) (16 mg, 33 [mu] mol, 1.31 mmol) in a sealed tube was added to a solution of tributyl (methoxy) ). The tube was flushed with nitrogen and sealed. The reaction mixture was stirred at 100 &lt; 0 &gt; C for 16 hours. The reaction mixture was diluted with EtOAc (5 mL) and 4M KF _(aq) (1 mL) was added. After stirring for 1 hour, the reaction mixture was filtered through Celite ™ and rinsed with EtOAc. The organic phase was rinsed with water (2 x 5 mL) and brine (5 mL) then dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (30 mg, 11%).

Example 160

3- (3-Cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxylic acid (ABR 239943)

MeOH / H ₂ O: a-methyl-3-stirred during the (1 1, 12 mL) (3-cyclopentyl-propane-amido) -4-oxo-3- (trifluoromethyl) -2,5,7- triaza To a solution of tricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10-tetraene-9-carboxylate (500 mg, 1.14 mmol) LiOH.H ₂ O (144 mg, 3.42 mmol). The reaction mixture was stirred at 60 &lt; 0 &gt; C for 16 h and then concentrated. The residue was dissolved in water and acidified to pH 1 using 1 M HCl _(aq) . The precipitate formed was collected by filtration and then rinsed with water and hexane to give the title compound as a brown solid (422 mg, 87%).

Example 161

3-Cyclopentyl- N - {9- [1- (methoxyimino) ethyl] -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl} propanamide (ABR 239950)

To a stirred solution of N - [9-acetyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Methylhydroxyl (2-chloro-2-fluoroaniline) was dissolved in pyridine (82 μL, 1.0 mmol) in dichloromethane Amine hydrochloride (92 mg, 1.1 mmol). The reaction was heated at 80 &lt; 0 &gt; C for 1 h and then concentrated. The residue was dissolved in EtOAc (15 mL) and water (15 mL). The phases were extracted with EtOAc (2 x 10 mL). The combined organic extracts were rinsed with brine (20 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (61 mg, 47%).

Example 162

3- (3-Cyclopentylpropanamido) - N -Methyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxamide (ABR 239951)

To a sealed tube was added 50% anhydrous propylphosphonic acid / EtOAc (90 mg, 0.14 mmol), MeCN (1.2 mL), triethylamine (66 L, 0.47 mmol) and 3- (3- cyclopentylpropanamido) Dioxa-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10-tetraen- Carboxylic acid (50 mg, 0.12 mmol). The reaction was stirred at room temperature for 30 minutes and then methylamine hydrochloride (8 mg, 0.1 mmol) was added. The reaction mixture was stirred for an additional 60 hours. The reaction mixture was diluted with EtOAc. And then drying the organic phase was diluted with 1M HCl _(aq) and Dublin (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) followed by silica chromatography using 0-10% MeOH in DCM as eluent to give the title compound as a brown solid (15 mg, 28% ).

Example 163

3-Cyclopentyl- N - [9-ethynyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239986)

To a stirred solution of 3-cyclopentyl- N- [4-oxo-3- (trifluoromethyl) -9- {2- [tris (propan- , the 5,7-triaza-tricyclo [6.4.0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] propanamide (100 mg, 0.18 mmol) solution, Under nitrogen at 0 &lt; 0 &gt; C, 1M TBAF / THF (232 L, 0.23 mmol) was added. The reaction was stirred at room temperature for 10 minutes. The reaction was cooled to 0 &lt; 0 &gt; C and treated with 1M TBAF / THF (232 [mu] L, 0.23 mmol). The reaction was stirred at room temperature for 1 hour and then concentrated. The residue was dissolved in DCM (10 mL), rinsed with water (5 mL) and brine (5 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica chromatography using 0-2% MeOH in DCM as eluent and then purified by automated reverse phase HPLC (low pH method A) to give the title compound as a brown solid (22 mg, 31 &lt; RTI ID = %).

Example 164

3-Cyclopentyl- N - [4-oxo-9- (trifluoromethoxy) -3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239991)

To a stirred solution of 3-cyclopentylpropanamide (98 mg, 0.69 mmol) in anhydrous DCM (10 mL) was added methyl 3,3,3-trifluoro-2-oxopropanoate (141 L, 1.38 mmol) , Pyridine (56 [mu] L, 0.69 mmol) was added at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. Thionyl chloride (50 [mu] L, 0.69 mmol) was added at 0 [deg.] C and then the reaction mixture was stirred at 0 &lt; 0 &gt; C for 1 hour. The reaction mixture was concentrated, and the residue was eluted through a silica short pad with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (5 mL) under nitrogen. Acyl intermediate was added to a solution of DMF (10 ml) in which 4- (trifluoromethoxy) -1H-1,3-benzodiazole-2-amine (125 mg, 0.58 mmol) was dissolved, Ethylamine (230 [mu] L, 1.73 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours and then concentrated. The residue was diluted in EtOAc (50 mL) and rinsed with saturated citric acid _(aq) (30 mL). The phases were extracted with EtOAc (50 mL). The combined organic extracts were rinsed with brine (2 x 15 mL), dried (MgSO ₄ ), filtered and concentrated. The crude product was triturated in DCM. A portion of this material was further purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (50 mg).

Example 165

3-Cyclopentyl- N - [9-cyclopropanesulfonamido-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239995)

To a solution of 3-cyclopentyl- N- [9-iodo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4. 0.0 &gt; ^2,6 ] dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (150 mg, 0.30 mmol) in a sealed tube was added cyclopropylsulfonamide , 0.36 mmol) followed by K ₂ CO ₃ (82 mg, 0.59 mmol). The prepared suspension was degassed with nitrogen and then added with di- tert -butyl [2 ', 4', 6'-tri (propan-2- yl) biphenyl- Followed by bis (chloro (prop-2-en-1-yl) palladium) (7 mg, 0.02 mmol). The reaction was degassed with nitrogen, sealed and then stirred at 80 &lt; 0 &gt; C for 3 hours. Additionally, as the die - tert - butyl - 2 ', 4', 6'-tri (propan-2-yl) biphenyl-2-yl] phosphonic plate (3 mg, 0.01 mmol) and bis (chloro (prop -2 -En-1-yl) palladium) (7 mg, 0.02 mmol). The reaction mixture was degassed and stirred at 80 &lt; 0 &gt; C for a further 16 hours. The reaction was then concentrated. The residue was dissolved in EtOAc (30 mL) and rinsed with 1 M HCl _(aq) (30 mL), water (2 x 30 mL) and brine (2 x 30 mL). The combined aqueous phases were extracted with EtOAc (30 mL). The combined organic extracts were rinsed with brine (30 mL), dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (24 mg, 16%).

Example 166

3- (3-Cyclopentylpropanamido) - N -Methanesulfonyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxamide (ABR 239996)

Sodium hydroxide (60%, 48 mg, 1.2 mmol) was added to a stirred solution of methanesulfonamide (114 mg, 1.2 mmol) in DMF (10 mL) at 0 C under nitrogen. After stirring for 15 min at 0 C, a solution of phenyl 3- (3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^{2 , 6} ] dodeca-1 (12), 6,8,10-tetraene-9-carboxylate (150 mg, 0.3 mmol) dissolved in DMF (2 mL). The reaction mixture was warmed to room temperature and heated at 50 &lt; 0 &gt; C. After 1 hour, the reaction mixture was cooled to 0 ℃, was quenched with saturated NH ₄ Cl _(aq). The reaction mixture was concentrated. The residue was dissolved in EtOAc (50 mL), which was rinsed with water (3 x 25 mL) and Dublin (2 x 25 mL), then dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (19 mg, 13%).

Example 167

3-Cyclopentyl- N - [9-methanesulfonamido-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239999)

To a stirred solution of N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4. 0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] -3-cyclopentyl-propanamide (200 mg, 0.44 mmol), methanesulfonamide (50 mg, 0.52 mmol ), di - tert - butyl - 2 ', 4', 6'-tri (propan-2-yl) biphenyl-2-yl] phosphonic plate (2 mg, 4 μmol), bis (chloro (prop -2 -en-1-yl) palladium) (5 mg, 13 μmol) and _{K 2 CO 3 (120 mg,} 0.87 mmol) was heated at 80 ℃ for 5 hours. To the reaction were added methanesulfonamide (50 mg, 0.52 mmol), di- tert -butyl [2 ', 4', 6'-tri (propan- ) and bis (chloro (prop-2-en-1-yl) palladium) (5 mg, 13 μmol) were reprocessed. Degassed, and heat-treated at 80 DEG C for 18 hours. The reaction was diluted with EtOAc (15 mL) and rinsed with 1 M HCl _(aq) (15 mL). The phases were extracted with EtOAc (2 x 15 mL). The combined organic extracts were rinsed with brine (30 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (22 mg, 11%).

Example 168

N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2 - [(2- methoxyethyl) amino] 240004)

To a stirred solution of 2-bromo-1,3-thiazole-4-carboxamide (2.93 g, 14.2 mmol) in DMF (80 mL) was added methyl 3,3,3-trifluoro- (4.42 g, 28.3 mmol) was added followed by pyridine (1.14 mL, 14.2 mmol) under nitrogen. The reaction was stirred at room temperature for 16 hours. Additional methyl 3,3,3-trifluoro-2-oxopropanoate (4.42 g, 28.3 mmol) was added and the reaction stirred for a further 4 h. Thionyl chloride (1.03 mL, 14.2 mmol) was added at 0 &lt; 0 &gt; C. The reaction was stirred at 0 &lt; 0 &gt; C for a further 2 h and then concentrated. The residue was eluted through a silica shortpot with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (10 mL) under nitrogen. Acyl intermediate was added to a solution of 4-bromo-1H-1,3-benzodiazole-2-amine (2.50 g, 11.8 mmol) dissolved in DMF (40 ml) followed by the addition of triethylamine mL, 14.2 mmol). The reaction mixture was stirred for a further 2 h and then concentrated. The residue was dissolved in EtOAc (200 mL), and then dried, rinse with 10% citric acid _(aq) (2 x 100 mL), water (2 x 100 mL) and Dublin (2 x 100 mL) (MgSO _4), filtered And concentrated. The crude product was purified by trituration in DCM to give 2-bromo- N- [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [ 6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10-tetraen-3-yl] -1,3- thiazole- 4- carboxamide and N- [9- (12), 6,8,10-tetraen-3- (4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Chloro-l, 3-thiazole-4-carboxamide (3.70 g).

To a sealed tube was added 2-bromo- N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Carboxamide with N - [9-bromo-4-oxo-3- (tri (4-hydroxyphenyl) fluoromethyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] -2-chloro-l (0.40 g), K ₂ CO ₃ (0.53 g, 3.8 mmol), 2-methoxyethan-1 -amine (327 μL, 3.81 mmol) and dioxane 5 mL). First, the reaction was heated at 130 DEG C for 3 hours. The reaction was then heated for a further 9 hours at 130 &lt; 0 &gt; C. During this period additional 2-methoxyethan-1 -amine (982 μL, 11.4 mmol) and K ₂ CO ₃ (1.58 g, 11.4 mmol) were added in portions while reacting at room temperature during the re-treatment. The reaction mixture was then heated at 130 &lt; 0 &gt; C for 16 h without further work-up and then concentrated. The residue was dissolved in EtOAc (50 mL) and rinsed with saturated NH ₄ Cl _(aq) (50 mL), water (50 mL) and brine (50 mL). The combined aqueous washes were extracted with EtOAc (25 mL) and these organic extracts were rinsed with brine (50 mL). Dry the combined organic extracts (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a yellow solid (130 mg).

Example 169

N - [9-acetyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2 - [(2- methoxyethyl) amino] 240005)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Yl) -2 - [(2-methoxyethyl) amino] -1,3-thiazole-4-carboxamide (110 mg, 0.21 mmol), palladium (8.7 mg, 0.02 mmol), K ₂ CO ₃ (41 mg, 0.30 mmol), 1- ( _2- methylpiperidine- (138 L, 1.06 mmol) and degassed DMF / water (4: 1, 1.3 ml) were charged under nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 3 h and then concentrated. The residue was dissolved in THF (20 mL) and 1M HCl _(aq) (5 mL) was added. The reaction was stirred at room temperature for 1 hour and then diluted with EtOAc (25 mL) and water (25 mL). The organic phase was rinsed with 1 M HCl _(aq) (25 mL), water (25 mL) and brine (25 mL), then dried (MgSO ₄ ) and filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (47 mg, 46%).

Example 170

3- (3,3-Difluoropyrrolidin-1-yl) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239907)

To a solution of N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca- Propan-2-enamide (125 mg, 0.37 mmol) in a sealed tube was added 3,3-difluoropyrrolidine Hydrochloride (69 mg, 0.48 mmol), silica (18 mg) and triethylamine (98 [mu] L, 0.74 mmol) were added. The reaction was heated at 80 &lt; 0 &gt; C for 3 hours. The silica was filtered off and the filtrate was concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (42 mg, 26%).

Example 171

N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (3- fluoroazetidin- 1- yl) propanamide (ABR 239909)

3- (3,3-difluoro-pyrrolidin-1-yl) - N - [(trifluoromethyl) 10,11-dimethyl-4-oxo-3--2,5,7- triaza tricyclo [6.4.0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] but using a manufacturing method of propanamide, 3-a 3-fluoro Loa jetties Dean hydrochloride , 3-difluoropyrrolidine hydrochloride (61%).

Example 172

3- (3,3-Difluoropiperidin-1-yl) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239911)

3- (3,3-difluoropyrrolidin-1-yl) -N- [10,11-dimethyl-4-oxo- 3- (trifluoromethyl) Tricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide but using 3,3-difluoropiperidine Hydrochloride was used instead of 3,3-difluoropyrrolidine hydrochloride (13%).

Example 173

N - [9-acetyl-10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239928)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] ), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (500 mg, 1.03 mmol), palladium (II) acetate (7 mg, 0.03 mmol) one bis (diphenylphosphino plate) (27 mg, 0.06 mmol) , K 2 CO 3 (184 mg, 1.33 mmol), 1- ( ethenyl the oxy) butane (667 ㎕, 5.13 mmol) and degassed DMF / water ( 4: 1, 4 ml) was charged under nitrogen. The reaction mixture was stirred at 100 ° C for 3 hours. (7 mg, 0.03 mmol), propane-1,3-diylbis (diphenylphosphane) (27 mg, 0.06 mmol) and 1- (ethenyloxy) butane (667 [ 5.13 mmol). The reaction was further heated at 100 &lt; 0 &gt; C for 13 h and then concentrated. The residue was dissolved in THF (25 mL) and 1M HCl _(aq) (10 mL) was added. The reaction was stirred at room temperature for 3 h and then diluted with EtOAc (100 mL). The phases were extracted with EtOAc (2 x 50 mL). The combined organic extracts were rinsed with brine (50 mL), dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by silica chromatography using 0-5% MeOH in DCM as eluent and then tritylation in DCM to give the title compound as a brown solid (160 mg, 35%).

Example 174

N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-methoxypyridine-3- carboxamide (ABR 239987)

To a stirred solution of 2-methoxypyridine-3-carboxamide (available under the method of PCT international application 2010101949) (300 mg, 1.97 mmol) in DMF (5 mL) was added methyl 3,3,3-tri Fluoro-2-oxopropanoate (0.24 mL, 2.4 mmol) was added followed by pyridine (0.16 mL, 2.0 mmol) under nitrogen. The reaction was stirred at room temperature for 16 hours. Thionyl chloride (0.14 mL, 2.0 mmol) was added at 0 &lt; 0 &gt; C. The reaction was stirred at 0 &lt; 0 &gt; C for 1 h and then concentrated. The residue was eluted through a silica shortpot with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (5 mL) under nitrogen. Acyl intermediate was added to a solution of 5,6-dimethyl-1H-benzimidazol-2-amine (254 mg, 1.58 mmol) dissolved in DMF (5 mL) followed by triethylamine (0.26 mL, 2.0 mmol). The reaction mixture was stirred for a further 4 h and then concentrated. The residue was dissolved in EtOAc (30 mL) and rinsed with saturated citric acid _(aq) (30 mL). The phases were extracted with EtOAc (2 x 20 mL). Rinse the combined organic extracts with water (2 x 20 mL) and Dublin (2 x 20 mL) then dried (MgSO _4), filtered, and concentrated. The crude product was purified by trituration in diethyl ether to give the title compound as a pink solid (215 mg, 30%).

Example 175

N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-hydroxypyridine-3- carboxamide (ABR 239989)

To a stirred solution of N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodecane Carboxamide (235 mg, 0.52 mmol) in tetrahydrofuran (10 mL) at 0 &lt; 0 &gt; C under nitrogen was added 1M Libromoboran / DCM (1.54 mL, 1.54 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction was then stirred for an additional 8 hours at room temperature. During this period, 1M tribromoborane / DCM (3.08 mL, 3.08 mmol) was added in portions during the reaction at 0 &lt; 0 &gt; C during the re-treatment. The reaction mixture was then cooled to 0 C and water (10 mL) and 2M HCl _(aq) (10 mL) were added. The prepared suspension was stirred at room temperature for 16 hours. The precipitate was collected via filtration and then rinsed with DCM (10 mL) and water (10 mL). The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (80 mg, 42%).

Example 176

N - [11-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239914)

To a solution of 3-cyclopentyl- N- [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] 12), 6,8,10-tetraen-3-yl] propanamide (2.5 g, 6.6 mmol) in DMF (5 mL) was added NBS (1.4 g, 7.9 mmol). The reaction mixture was stirred at room temperature for 5 hours and then concentrated. The residue was dissolved in EtOAc (250 mL), which was rinsed with water (2 x 250 mL) and Dublin (2 x 150 mL) then dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 0-10% MeOH as eluent and then purified by subsequent automated reverse phase HPLC (low pH method A) to give the title compound as a yellow solid (1.2 g, 40% ).

Example 177

N - [10-bromo-9-fluoro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239927)

Methyl 3,3,3-trifluoro-2-oxopropanoate (0.40 mL, 3.9 mmol) was added to a stirred solution of 3-cyclopentylpropanamide (368 mg, 2.61 mmol) in DMF (10 mL) Then pyridine (0.21 mL, 2.6 mmol) was added under nitrogen. The reaction was stirred at room temperature for 1.5 hours. Thionyl chloride (0.19 mL, 2.6 mmol) was added at 0 占 and the reaction mixture was then stirred at 0 占 폚 for 1.5 hours. The reaction mixture was concentrated and eluted through a silica short pad with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (5 mL) under nitrogen. Acyl intermediate was added to a solution of 5-bromo-4-fluoro-lH-l, 3-benzodiazole-2-amine (500 mg, 2.17 mmol) dissolved in DMF , Triethylamine (0.35 mL, 2.6 mmol) was added. The reaction mixture was stirred for 2 hours and then concentrated. The residue was dissolved in EtOAc (20 mL) and rinsed with 10% citric acid _(aq) (20 mL). The phases were extracted with EtOAc (2 x 20 mL). Rinse the combined organic extracts with 10% citric acid _(aq) (2 x 20 mL) and Dublin (2 x 20 mL) then dried (MgSO _4), filtered, and concentrated. The crude product was triturated in DCM to give the title compound as a brown oil (401 mg, 39%).

Example 178

N - [9-Bromo-10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239933)

To a solution of 3-cyclopentylpropanamide (0.44 g, 3.1 mmol) in anhydrous DCM (17 mL) was added pyridine (250 L, 3.10 mmol) followed by methyl 3,3,3-trifluoro- (967 mg, 6.20 mmol) was added under nitrogen. The reaction was stirred at room temperature for 2 hours. Thionyl chloride (245 L, 3.10 mmol) was added at 0 &lt; 0 &gt; C. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 1 hour and then filtered through a silica short pad with DCM and under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (14 mL) under nitrogen. A solution of 4-bromo-5-methoxy-1H-1,3-benzodiazol-2-amine (625 mg, 2.6 mmol) in DMF (3 mL) was added followed by triethylamine (432 μL, 3.1 mmol ). The reaction was stirred for 16 h and then concentrated. The residue was dissolved in EtOAc, rinsed with brine (4 x), dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by trituration in DCM to give the title compound as a yellow solid (0.76 g, 60%).

Example 179

3-Cyclopentyl- N - [9-fluoro-10- (1 -hydroxyethyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239937)

To a sealed tube was added N - [10-bromo-9-fluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] (156 mg, 0.30 mmol), palladium (II) acetate (2 mg, 0.01 mmol), propane-1,2- 1,3-yl-bis (diphenylphosphino plate) (8 mg, 0.02 mmol) , K 2 CO 3 (54 mg, 0.39 mmol), 1- ( ethenyl oxy) butane (196 ㎕, 1.51 mmol) and degassing DMF / water (3: 1, 4 ml) was charged under nitrogen. The reaction mixture was stirred at 100 ° C for 3 hours. (2 mg, 0.01 mmol), propane-1,3-diyl bis (diphenylphosphane) (8 mg, 0.02 mmol), K ₂ CO ₃ (27 mg, 0.2 mmol) and 1- (Ethenyloxy) butane (78 [mu] L, 0.6 mmol) was added. The reaction was degassed and stirred for 16 h at 100 &lt; 0 &gt; C. The reaction was concentrated. The resulting residue was dissolved in EtOAc (10 mL) and rinsed with brine (10 mL). The phases were extracted with EtOAc (2 x 15 mL). The combined organic extracts were rinsed with brine (2 x 15 mL), dried (MgSO ₄ ), filtered and concentrated to give N - [10-acetyl-9-fluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10-tetraen- 3- yl] -3-cyclopentylpropanamide as a brown solid (152 mg).

To a stirred solution of N - [10-acetyl-9-fluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^{2, 6]} dodeca-1 (12), 6,8,10- tetraen-3-yl] -3-cyclopentyl-propane amide (25%, 152 mg, 0.09 mmol) solution, under nitrogen at 0 ℃, sodium Tetrahydroborate (33 mg, 0.86 mmol) was added. The prepared solution was allowed to warm to room temperature over 16 hours. Additional sodium tetrahydroborate (49 mg, 1.3 mmol) was added at 0 &lt; 0 &gt; C. The reaction was warmed to room temperature over 4 hours and concentrated. The residue was dissolved in EtOAc (10 mL) and rinsed with brine (10 mL). The phases were extracted with EtOAc (2 x 10 mL). Rinse the combined organic extracts were Dublin (2 x 10 mL) then dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 0-50% MeOH in DCM as eluent and further purification by automated reverse phase HPLC (high pH) to give the title compound as a white solid (8 mg, 19% ).

Example 180

N - [9-acetyl-10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239946)

To a sealed tube was added N - [9-bromo-10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] car-1 (12), 6,8,10- tetraen-3-yl] -3-cyclopentyl-propanamide (2.00 g, 0.40 mmol), Pd (PPh 3) 2 Cl 2 (29 mg, 0.04 mmol) , Tributyl (1-ethoxyethenyl) stannane (275 l, 0.80 mmol) and toluene (2 mL) were charged under nitrogen. First, the reaction was stirred at 110 [deg.] C for 16 hours. The reaction was then heated for a further 30 hours. During this period, the additional material was added portionwise at room temperature while the reaction in the process the _{Pd (PPh 3) 2 Cl 2} (44 mg, 0.06 mmol) in. The reaction mixture was diluted with 2M HCl _(aq) (2 mL) and stirred at room temperature for 1 hour. EtOAc was added and the resulting suspension was filtered through Celite ™. Rinse the organic phase with water, filtered, Dublin dried (MgSO _4), filtered, and concentrated. The crude product was first purified by automated reversed phase HPLC (low pH method A). Further purification by silica chromatography with 0-50% DCM / MeOH / AcOH / H ₂ O (90: 18: 3: 2) in DCM as eluent followed by trituration in cold DCM gave the title compound Obtained as a white solid (33 mg, 18%).

Example 181

N - [9-Bromo- 11-chloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239916)

To a stirred solution of 3-cyclopentylpropanamide (0.61 g, 4.29 mmol) in anhydrous DCM (24 mL) was added pyridine (346 L, 4.29 mmol) followed by methyl 3,3,3-trifluoro- Oxo-propanoate (1.34 g, 8.58 mmol) was added under nitrogen. The reaction mixture was stirred for 2 hours. Thionyl chloride (311 [mu] L, 4.29 mmol) was added at 0 [deg.] C, then the reaction mixture was stirred at 0 [deg.] C for 1 hour. The reaction mixture was eluted through a silica shortpot with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (20 mL) under nitrogen. A solution of 4-bromo-6-chloro-lH-l, 3-benzodiazole-2-amine (881 mg, 3.57 mmol) in DMF (4 mL) was added followed by triethylamine (343, 2.46 mmol) Was added. The reaction mixture was stirred at room temperature for 16 hours and then concentrated. The residue was diluted with EtOAc and rinsed with brine (4 x). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was triturated with DCM to give the title compound as a yellow solid (884 mg, 50%).

Example 182

N - [9-acetyl-11-chloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239936)

N - [9- acetyl-10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca-1 (12) , 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide but using N - [9-bromo-11-chloro-4- Methyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10-tetraen- 3- yl] -3-cyclopentylpropanamide N - [9-Bromo-10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] ), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide. Reprocessing may not be necessary. The crude product was purified by automated reversed phase HPLC (low pH method A) (23%).

Example 183

N - [11-bromo-9-fluoro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239926)

Methyl 3,3,3-trifluoro-2-oxopropanoate (878 L, 8.61 mmol) was added to a stirred solution of 3-cyclopentylpropanamide (1.01 g, 7.17 mmol) in DMF (20 mL) Then pyridine (578 [mu] L, 7.17 mmol) was added under nitrogen. The reaction was stirred at room temperature for 16 hours. Thionyl chloride (521 [mu] L, 7.17 mmol) was added at 0 [deg.] C, then the reaction mixture was stirred at 0 [deg.] C for 1 hour. The reaction mixture was concentrated and eluted through a silica short pad with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (20 mL) under nitrogen. A solution of 6-bromo-4-fluoro-1H-1,3-benzodiazole-2-amine (1.32 g, 5.74 mmol) in DMF (20 mL) was added followed by triethylamine (1.15 mL, 8.61 mmol ). The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in EtOAc (200 mL), followed by water (3 x 100 mL) and then dried to rinse Dublin _{(100 mL) (Na 2 SO} 4) , filtered, and concentrated. The crude product was triturated in DCM to give the title compound as a white solid (1.20 g, 44%).

Example 184

N - [11-acetyl-4-oxo-3,9-bis (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239942)

To a sealed tube was added N - [11-bromo-4-oxo-3,9-bis (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] 1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (150 mg, 0.28 mmol), palladium (II) acetate (2 mg, 8.5 μmol) 3-yl-bis (diphenylphosphino plate) (8 mg, 0.02 mmol) , K 2 CO 3 (51 mg, 0.37 mmol), 1- ( ethenyl oxy) butane (185 ㎕, 1.42 mmol) and degassed DMF / Water (3: 1, 4 mL) was charged under nitrogen. First, the reaction was stirred at 100 &lt; 0 &gt; C for 4 hours. The reaction was then heated for a further 4 hours. During this period additional palladium (II) acetate (2 mg, 8.5 μmol), propane-1,3-diyl bis (diphenylphosphane) (8 mg, 0.02 mmol) and 1- (ethenyloxy) (185 [mu] L, 1.42 mmol) was added portionwise while reacting at room temperature during the reprocessing. The reaction was cooled to room temperature and then concentrated. The residue was dissolved in THF (15 mL) and 1M HCl _(aq) (4 mL) was added. The reaction was stirred at room temperature for 20 min and then concentrated. The residue was dissolved in EtOAc (10 mL) and rinsed with brine (10 mL). The phases were extracted with EtOAc (15 mL). Rinse the combined organic extracts were Dublin (15 mL) and then dried (MgSO _4), filtered, and concentrated. The crude product was purified by reverse phase C18 chromatography using an acidic eluent. Further purification by trituration in DCM followed by purification by automated reverse phase HPLC (high pH) gave the title compound as a white solid (29 mg, 21%).

Example 185

N - [11-chloro-10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide and N - [10-chloro-11-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239941)

To a stirred solution of 3-cyclopentylpropanamide (128 mg, 0.90 mmol) in DCM (1.5 mL) was added methyl 3,3,3-trifluoro-2-oxopropanoate (138 L, 1.35 mmol) Then pyridine (73 [mu] L, 0.9 mmol) was added under nitrogen. The reaction was stirred for 1 hour at room temperature. Thionyl chloride (66 [mu] L, 0.90 mmol) was added at 0 [deg.] C. The reaction was stirred at 0 &lt; 0 &gt; C for 1 hour and then filtered through a silica short pad eluting with DCM and under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (2 mL) under nitrogen. Acyl intermediate was added to a solution of 6-chloro-5-methoxy-1H-1,3-benzodiazole-2-amine (150 mg, 0.75 mmol) dissolved in DMF (2 mL) Ethylamine (120 [mu] L, 0.90 mmol) was added. The reaction mixture was stirred for a further 4 h and then concentrated. The residue was dissolved in EtOAc (15 mL) and rinsed with saturated citric acid _(aq) (15 mL). The phases were extracted with EtOAc (15 mL). The combined organic extracts were rinsed with brine (2 x 15 mL), dried (MgSO ₄ ), filtered and concentrated to give the title compound as a brown solid (1 mg) as a 1: 1 mixture of positional isomers.

Example 186

3-Cyclopentyl- N - [9- (4-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239731)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] ), 6,8,10- tetraen-3-yl] -3-cyclopentyl-propanamide (50 mg, 0.11 mmol), (4- methoxyphenyl) boronic acid (21 mg, 0.14 mmol), Na 2 CO ₃ (21 mg, 0.2 mmol), water (0.4 mL), DME (1.4 mL) and EtOH (0.6 mL). The solution was degassed with nitrogen. Was added _{Pd (PPh 3) 4 (7} mg, 0.01 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 6 hours. The reaction mixture was diluted with EtOAc (10 mL) and rinsed with water (5 mL). The phases were extracted with EtOAc (3 x 5 mL). Rinse the combined organic extracts were Dublin (2 x 15 mL) then dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (18 mg, 34%).

Example 187

3-Cyclopentyl- N Pyrazol-4-yl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239732)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] ), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (100 mg, 0.22 mmol) 0.3 mmol), Na ₂ CO ₃ (42 mg, 0.39 mmol), water (0.8 mL), DME (2.8 mL) and EtOH (1.2 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (25 mg, 0.02 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 2 hours. The reaction mixture was diluted with EtOAc (10 mL) and rinsed with water (10 mL). The phases were extracted with EtOAc (2 x 10 mL). Rinse the combined organic extracts were Dublin (2 x 10 mL) then dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (42 mg, 41%).

Example 188

3-Cyclopentyl- N - [9- (6-methoxypyridin-3-yl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239944)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] 3-yl] -3-cyclopentylpropanamide (160 mg, 0.15 mmol) and (6-methoxypyridin-3- yl) boronic acid (66 mg, 0.44 mmol) , Na ₂ CO ₃ (66 mg, 0.69 mmol), water (1.8 mL), DME (6.0 mL) and EtOH (2.5 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (40 mg, 0.04 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 2 h and then concentrated. The residue was dissolved in EtOAc (100 mL) and rinsed with water (50 mL), saturated citric acid _(aq) (50 mL) and brine (2 x 10 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by tritylation in DCM and subsequently purified by automated HPLC (low pH method A) to give the title compound as a white solid (100 mg, 59%).

Example 189

3-Cyclopentyl- N - [9- (3-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239948)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] ), 6,8,10- tetraen-3-yl] -3-cyclopentyl-propanamide (100 mg, 0.22 mmol), (3- methoxyphenyl) boronic acid (46 mg, 0.3 mmol), Na 2 CO ₃ (46 mg, 0.44 mmol), water (0.8 mL), DME (2.8 mL) and EtOH (1.2 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (13 mg, 0.01 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 16 hours. The reaction mixture was concentrated. The residue was dissolved in EtOAc (50 mL) and rinsed with water (25 mL), 1 M HCl _(aq) (25 mL) and brine (25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a yellow solid (44 mg, 42%).

Example 190

3-Cyclopentyl- N - [9- (1,3-oxazol-2-yl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239953)

To a solution of N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca- 1 (12), 6,8,10- tetraen-3-yl] -3-cyclopentyl-propanamide (200 mg, 0.44 mmol), sodium tert - butoxide (84 mg, 0.87 mmol) and Pd (PPh ₃ ) ₄ (25 mg, 0.02 mmol) in dichloromethane was added 1,3-oxazole (43 L, 0.65 mmol). The reaction was flushed with nitrogen, sealed and then heated at 100 &lt; 0 &gt; C for 4 hours. The reaction was treated with sodium tert -butoxide (84 mg, 0.87 mmol), Pd (PPh ₃ ) ₄ (25 mg, 0.02 mmol) and 1,3-oxazole (43 μl, 0.65 mmol) And further heated at 100 DEG C for 3.5 hours. The reaction was diluted with EtOAc (30 mL) and rinsed with water (15 mL) and brine (15 mL). The organic phase was dried (Na ₂ SO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (83 mg, 43%).

Example 191

N - [9- (4- tert -Butylphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239954)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] ), 6,8,10- tetraen-3-yl] -3-cyclopentyl-propanamide (50 mg, 0.11 mmol), (4- tert - butylphenyl) boronic acid (24 mg, 0.14 mmol), Na 2 the _{CO 3 (21 mg, 0.20 mmol} ), water (0.90 mL), DME (3.00 mL) and EtOH (1.25 mL) were charged. The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (13 mg, 0.01 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 18 hours. The reaction mixture was filtered through Celite (TM), rinsed with MeOH (30 mL) and the filtrate was concentrated. The residue was dissolved in EtOAc (20 mL), which was rinsed with water (30 mL), saturated citric acid _(aq) (30 mL) and Dublin (30 mL) and then dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 0-100% EtOAc in heptane as eluent to give the title compound as a white solid (39 mg, 70%).

Example 192

N - [9- (4-cyanophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239956)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] ), 6,8,10- tetraen-3-yl] -3-cyclopentyl-propanamide (50 mg, 0.11 mmol), (4- cyanophenyl) boronic acid (21 mg, 0.14 mmol), Na 2 CO ₃ (21 mg, 0.20 mmol), water (0.90 mL), DME (3.00 mL) and EtOH (1.25 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (13 mg, 0.01 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 18 hours. The reaction mixture was filtered through Celite (TM), rinsed with MeOH (30 mL), and the filtrate was concentrated. The residue was dissolved in EtOAc (20 mL), which was rinsed with water (30 mL), saturated citric acid _(aq) (30 mL) and Dublin (30 mL) and then dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 0-100% EtOAc in heptane as eluent to give the title compound as a brown solid (21 mg, 40%).

Example 193

3-Cyclopentyl- N - [9- (4-nitrophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239957)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] ), 6,8,10- tetraen-3-yl] -3-cyclopentyl-propanamide (100 mg, 0.22 mmol), (4- nitrophenyl) boronic acid (46 mg, 0.27 mmol), Na 2 CO 3 (42 mg, 0.39 mmol), water (0.90 mL), DME (3.00 mL) and EtOH (1.25 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (25 mg, 0.02 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 18 hours. The reaction mixture was filtered through Celite (TM), rinsed with MeOH (30 mL), and the filtrate was concentrated. The residue was dissolved in EtOAc (20 mL), which was rinsed with water (30 mL), saturated citric acid _(aq) (30 mL) and Dublin (30 mL) and then dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 0-100% EtOAc in heptane as eluent to give the title compound as an orange solid (70 mg, 64%).

Example 194

N - [9- (4-aminophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239965)

To a solution of 3-cyclopentyl- N- [9- (4-nitrophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4 .0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] propanamide (50 mg, 0.10 mmol) tin (II) chloride dihydrate in water (86 mg, 0.38 solution mmol). The reaction was heated at 70 &lt; 0 &gt; C for 18 hours. The reaction was cooled to room temperature, diluted with EtOAc (10 mL), filtered through Celite (TM) and rinsed with EtOAc (30 mL). The filtrate was concentrated. The crude product was loaded onto an acidic SCX-2 column, rinsed with 50% MeOH in DCM and then eluted with 3.5 M ammonia / MeOH. Purification by automated reverse phase HPLC (low pH method A) then gave the title compound as a brown solid (8 mg, 17%).

Example 195

3-Cyclopentyl- N - [4-oxo-9-phenyl-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239967)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] ), 6,8,10- tetraen-3-yl] -3-cyclopentyl-propanamide (150 mg, 0.32 mmol), phenylboronic acid (55 mg, 0.45 mmol), Na 2 CO 3 (68 mg, 0.64 mmol), water (0.7 mL), DME (1.4 mL) and EtOH (0.6 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (37 mg, 0.03 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction mixture was stirred at 100 ° C for 3 hours. Additional Phenylboronic acid (27 mg, 0.22 mmol), Na ₂ CO ₃ (34 mg, 0.32 mmol) and Pd (PPh ₃ ) ₄ (18 mg, 0.02 mmol) were added and the reaction stirred at 100 ° C. for 16 h Respectively. The reaction mixture was concentrated. The residue was dissolved in EtOAc (25 mL) and rinsed with brine (25 mL). The phases were extracted with EtOAc (25 mL). The combined organic extracts were rinsed with brine (2 x 50 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as an orange solid (47 mg, 32%).

Example 196

3-Cyclopentyl- N - [9- (2-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239970)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] ), 6,8,10- tetraen-3-yl] -3-cyclopentyl-propanamide (100 mg, 0.22 mmol), (2- methoxyphenyl) boronic acid (46 mg, 0.3 mmol), Na 2 CO ₃ (46 mg, 0.44 mmol), water (0.8 mL), DME (2.8 mL) and EtOH (1.2 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (13 mg, 0.01 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 16 hours. The reaction mixture was concentrated. The residue was dissolved in EtOAc (50 mL) and rinsed with water (25 mL), 1 M HCl _(aq) (25 mL) and brine (25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (80 mg, 75%).

Example 197

2-hydroxy- N - [9- (4-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] pyridine-3- carboxamide (ABR 239988)

To a sealed tube was added N - [9- (4-bromophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Car- 1 (12), 6,8,10-tetraen-3-yl] -2-hydroxypyridine- (47 mg, 0.31 mmol), Na ₂ CO ₃ (46 mg, 0.44 mmol), water (0.2 mL), DME (2.8 mL) and EtOH (100 mg, 0.22 mmol) (1.2 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (13 mg, 0.01 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 4 hours. (23 mg, 0.15 mmol), Na ₂ CO ₃ (46 mg, 0.44 mmol) and Pd (PPh ₃ ) ₄ (13 mg, 0.01 mmol) were added and the reaction was quenched by addition of (4-methoxyphenyl) boronic acid The mixture was further stirred at 100 ° C for 16 hours. The reaction mixture was concentrated. The residue was dissolved in EtOAc (25 mL) and rinsed with water (25 mL). The phases were extracted with EtOAc (2 x 20 mL) and IPA / CHCl ₃ (1: 1, 5 x 20 mL). Dry the combined organic extracts (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (high pH) to give the title compound as a white solid (24 mg, 22%).

Example 198

3-Cyclopentyl- N - [9- (2-hydroxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239978)

To a stirred solution of 3-cyclopentyl- N- [9- (2-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [ 6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (55 mg, 0.11 mmol) in DMF (5 mL) was added IM boron tribromide / DCM (0.34 mL, 0.34 mmol) under nitrogen. First, the reaction mixture was stirred at room temperature for 1 hour. The reaction was then stirred for an additional 4 hours. During this period an additional 1M boron tribromide / DCM (1.02 mL, 1.02 mmol) was added in portions. The reaction was then quenched with water at 0 &lt; 0 &gt; C. The organic phase was rinsed with _{1M HCl (aq) (25 mL} ) and water (25 mL), then dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (29 mg, 54%).

Example 199

3-Cyclopentyl- N - [4-oxo-9- (1H-1,2,3,4-tetrazol-5-yl) -3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239990)

To a stirred solution of N - [9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca- (500 mg, 1.23 mmol) and dibutyl (oxo) stannane (353 [mu] L, 1.23 mmol) in tetrahydrofuran In a sealed tube, azido (trimethyl) silane (490 [mu] L, 3.70 mmol) was added under nitrogen. The reaction was heated at 130 &lt; 0 &gt; C for 1.5 h. The reaction was diluted with MeOH (10 mL) at room temperature. The reaction was stirred for 2 hours and then concentrated. The crude product was purified by silica chromatography using 0-20% MeOH in DCM as eluent to give the title compound as a beige solid (142 mg, 25%).

Example 200

3- [3- (3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-9-yl] benzoic acid (ABR 239992)

To a stirred solution of methyl 3- [3- (3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4. 0.0 ^2,6] dodeca-a-1 (12), 6,8,10- tetraen-9-yl] benzoate (48 mg, 0.09 mmol), 2M NaOH _(aq) (0.28 mL, 0.56 mmol) to a solution . The reaction mixture was stirred at 50 &lt; 0 &gt; C for 4 h and then concentrated. The residue was dissolved in water and acidified to pH 2 using 1 M HCl _(aq) . The precipitate formed was collected by filtration and the crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a yellow solid (14 mg, 30%).

Example 201

N - [9- (4-chlorophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 240000)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] ), 6,8,10- tetraen-3-yl] -3-cyclopentyl-propanamide (100 mg, 0.22 mmol), (4- chlorophenyl) boronic acid (43 mg, 0.27 mmol), Na 2 CO 3 (42 mg, 0.39 mmol), water (0.20 mL), DME (1.00 mL) and EtOH (0.35 mL) and the solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (25 mg, 0.02 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 18 hours. The reaction mixture was filtered through Celite (TM), rinsed with MeOH (30 mL), and the filtrate was concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a yellow solid (60 mg, 56%).

Example 202

3-Cyclopentyl- N - [9- (4-methylphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 240001)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] (37 mg, 0.27 mmol) and Na ₂ CO ₃ (42 mg, 0.27 mmol) in DMF (100 mg, 0.22 mmol) and 6,8,10-tetraen- mg, 0.39 mmol), water (0.20 mL), DME (1.00 mL) and EtOH (0.35 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (25 mg, 0.02 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 18 hours. The reaction mixture was filtered through Celite (TM), rinsed with MeOH (30 mL), and the filtrate was concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a yellow solid (50 mg, 49%).

Example 203

3-Cyclopentyl- N - [9- (3,4-dichlorophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 240002)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] (52 mg, 0.27 mmol) was dissolved in a mixture of Na ₂ (100 mL) and tetrahydrofuran filling the _{CO 3 (42 mg, 0.39 mmol} ), water (0.20 mL), DME (1.00 mL) and EtOH (0.35 mL) and the solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (25 mg, 0.02 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 18 hours. The reaction mixture was filtered through Celite (TM), rinsed with MeOH (30 mL), and the filtrate was concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (56 mg, 49%).

Example 204

3-Cyclopentyl- N - [9- (3,4- dihydro-2H-pyran-5-yl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239733)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] ), 6,8,10-tetraen-3-yl] -3- cyclopentylpropanamide (50 mg, 0.11 mmol), 4- (4,4,5,5-tetramethyl- dioxaborolan-2-yl) -3,6-dihydro -2H- pyran (30 mg, 0.14 mmol), Na 2 CO 3 (21 mg, 0.20 mmol), water (0.4 mL), DME (1.4 mL) And EtOH (0.6 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (13 mg, 0.01 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 18 hours. The reaction mixture was diluted with EtOAc (10 mL) and rinsed with water (10 mL). The phases were extracted with EtOAc (2 x 10 mL). The combined organic extracts were rinsed with brine (2 x 10 mL), dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a brown solid (10 mg, 20%).

Example 205

3-Cyclopentyl- N Pyrazol-4-yl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [ 6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239729)

In a sealed tube, N - [9- bromo -10,11- (trifluoromethyl) dimethyl-4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (75 mg, 0.15 mmol), (1- methyl -1H- pyrazol-4-yl) boronic acid (24 mg, 0.19 mmol), Na 2 CO 3 (29 mg, 0.28 mmol), water (0.8 mL), DME (2.8 mL) and EtOH (1.2 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (18 mg, 0.02 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 2 hours. The reaction mixture was concentrated. The residue was dissolved in EtOAc (100 mL), which was rinsed with water (50 mL), saturated citric acid _(aq) (50 mL) and Dublin (50 mL) and then dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (35 mg, 47%).

Example 206

3-Cyclopentyl- N - [10,11-dimethyl-4-oxo-9- (1,2-thiazol-4-yl) -3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4. 0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239738)

In a sealed tube, N - [9- bromo -10,11- (trifluoromethyl) dimethyl-4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (75 mg, 0.15 mmol) Sabo Rolando 2-yl) -1,2-thiazole (42 mg, 0.20 mmol), Na 2 CO 3 (29 mg, 0.28 mmol), water (0.8 mL), DME (2.8 mL) and EtOH (1.2 mL ). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (18 mg, 0.02 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 2 hours. The reaction mixture was concentrated. The residue was dissolved in EtOAc (100 mL), which was rinsed with water (50 mL), saturated citric acid _(aq) (50 mL) and Dublin (50 mL) and then dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (29 mg, 38%).

Example 207

3-Cyclopentyl- N - [9- (furan-3-yl) -10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239739)

In a sealed tube, N - [9- bromo -10,11- (trifluoromethyl) dimethyl-4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (75 mg, 0.15 mmol), (furan- 0.2 mmol), Na ₂ CO ₃ (29 mg, 0.28 mmol), water (0.8 mL), DME (2.8 mL) and EtOH (1.2 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (18 mg, 0.02 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 2 hours. The reaction mixture was concentrated. The residue was dissolved in EtOAc (100 mL), which was rinsed with water (50 mL), saturated citric acid _(aq) (50 mL) and Dublin (50 mL) and then dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (18 mg, 25%).

Example 208

N - [9- (4-methoxyphenyl) -10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] acetamide (ABR 239929)

In a sealed tube, N - [9- bromo -10,11- (trifluoromethyl) dimethyl-4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] acetamide (100 mg, 0.25 mmol), (4- methoxyphenyl) boronic acid ₂ CO ₃ (47 mg, 0.44 mmol), water (0.9 mL), DME (3.0 mL) and EtOH (1.3 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (29 mg, 0.03 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 2 hours. The reaction mixture was concentrated. The residue was dissolved in EtOAc (100 mL), which was rinsed with water (50 mL), saturated citric acid _(aq) (50 mL) and Dublin (50 mL) and then dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (28 mg, 26%).

Example 209

3-Cyclopentyl- N - [9-fluoro-10- (4-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239924)

To a sealed tube was added N - [10-bromo-9-fluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] 3-yl] -3-cyclopentylpropanamide (194 mg, 0.39 mmol) and (4-methoxyphenyl) boronic acid (90 mg, 0.59 mmol ), Na ₂ CO ₃ (84 mg, 0.79 mmol), water (0.40 mL), DME (1.50 mL) and EtOH (0.50 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (46 mg, 0.04 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 16 hours. Add (4-methoxyphenyl) boronic acid (45 mg, mmol 0.30), Na ₂ CO ₃ (mg 42, 0.38 mmol) and Pd (PPh _{3), 4} (23 mg, mmol 0.02) was added. The solution was degassed with nitrogen and the tube sealed. The reaction mixture was stirred at 100 ° C for 3 hours. The reaction mixture was concentrated. The residue was dissolved in EtOAc (10 mL) and rinsed with water (10 mL). The phases were extracted with EtOAc (2 x 10 mL). The combined organic extracts were rinsed with water (15 mL) and brine (2 x 15 mL), dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by silica chromatography using 0-5% MeOH in DCM as eluent and triturated in MeOH to give the title compound as a cream solid (11 mg, 5%).

Example 210

3-Cyclopentyl- N - [11- (4- methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239923)

To a sealed tube was added N - [11-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] ), 6,8,10- tetraen-3-yl] -3-cyclopentyl-propanamide (200 mg, 0.44 mmol), (4- methoxyphenyl) boronic acid (83 mg, 0.54 mmol), Na 2 CO ₃ (83 mg, 0.78 mmol), water (1.80 mL), DME (6.0 mL) and EtOH (1.50 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (50 mg, 0.04 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction mixture was stirred at 100 ° C for 3 hours. The reaction mixture was concentrated. The residue was dissolved in EtOAc (100 mL), washed with water (50 mL), saturated citric acid _(aq) (50 mL), water, rinse with (50 mL) and Dublin (50 mL) and then dried (MgSO ₄₎ and filtered , &Lt; / RTI &gt; The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a beige solid (74 mg, 35%).

Example 211

(a) diastereomer 1: (2S) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2- (3-methylbutoxy) propanamide (ABR 239949)

(b) diastereomer 2: (2S) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2- (3-methylbutoxy) propanamide (ABR 239952)

In ethanol (10 mL) (2S) - N - [10,11- ( trifluoromethyl) dimethyl-4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2 - [(3- methylbut-2- en- 1- yl) oxy] propanamide (250 mg, 0.589 mmol The flask filled with the solution was evacuated and flushed with nitrogen (x 3). To the stirred solution was added 10% Pd / C (35 mg, 0.33 mmol). The flask was evacuated and flushed with nitrogen (x 3), then evacuated again and flushed with hydrogen (x 3). After stirring for 20 hours, the reaction was treated with 10% Pd / C (10 mg, 0.09 mmol) and stirred for 2 hours under a hydrogen atmosphere. The reaction was then filtered through Celite (TM), rinsed with EtOH and concentrated. The crude product was purified by silica chromatography using 0-5% MeOH in DCM as eluent and then purified by automated reverse phase HPLC (low pH method A) to give the diastereoisomer 1 as an amorphous solid Obtained as a white diastereomer as a single diastereomer (34 mg, 14%), diastereoisomer 2 was obtained as a white solid as a single diastereomer with undetermined stereochemistry at the quarter center (29 mg, 11 %).

(c) diastereomer 3: (2R) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2- (3-methylbutoxy) propanamide (ABR 239958)

(d) diastereomer 4: (2R) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2- (3-methylbutoxy) propanamide (ABR 239959)

(2S) - N - [10,11- ( trifluoromethyl) dimethyl-4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca-1 ( 12), 6,8,10- tetraen-3-yl] -2- (3-methylbutoxy), but using the preparation of propanamide, (2R) - N - [ 10,11- dimethyl-4 6-yl) -oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10- ] -2- (trifluoromethyl) - 10,11-dimethyl-4-oxo-3 - [(3-methyl-2-boot-en-1-yl) oxy] propanamide the (2S) - N -2,5- triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10-tetraen-3-yl] -2 - [(3- 2-en-1-yl) oxy] propanamide. This was purified to give the diastereoisomer 3 as a white solid (8.8%) as a single diastereomer with undetermined stereochemistry at the quarter center and the diastereomer 4 to the quarter center with undefined stereochemistry Obtained as a white solid (6%) as a single diastereomer.

Example 212

(a) diastereomer 1: (2R) -2- (3-chlorophenoxy) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239968)

(b) diastereoisomer 2: (2R) -2- (3-chlorophenoxy) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239969)

To a stirred solution of (2R) -2- (3-chlorophenoxy) propanamide (0.22 g, 1.1 mmol) in DMF (5 mL) was added methyl 3,3,3-trifluoro-2-oxopropanoate 0.16 mL, 1.6 mmol) was added followed by pyridine (0.09 mL, 1.1 mmol) under nitrogen. The reaction was stirred at room temperature for 2 hours. Thionyl chloride (0.08 mL, 1.1 mmol) was added at 0 &lt; 0 &gt; C. The reaction was stirred at 0 &lt; 0 &gt; C for 1 h and then concentrated. The residue was eluted through a silica shortpot with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (5 mL) under nitrogen. Acyl intermediate was added to a solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (0.14 g, 0.87 mmol) dissolved in DMF (5 ml) (0.17 mL, 1.3 mmol). The reaction mixture was stirred for a further 3 h and then concentrated. The residue was dissolved in EtOAc (50 mL), and then dried, rinse with 10% citric acid _{(aq) (2 x 25 mL} ), water (3 x 25 mL) and Dublin (3 x 25 mL) (MgSO _4), filtered And concentrated. The crude product was purified by silica chromatography using 1-3% MeOH in DCM as eluent and then purified by automated reversed-phase HPLC (low pH method A) to afford the diastereomer 1 to the quarter center with undetermined stereochemistry (33 mg, 8%) as a single diastereomer with a single stereoisomer, and diastereomer 2 as a single diastereomer with undetermined stereochemistry at the quarter center (32 mg , 6%).

Example 213

(2S) - N - [9-acetyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-cyclohexylpropanamide (ABR 239985)

In a closed tube, (2S) - N - [ 9- bromo-4-oxo-3- (trifluoromethyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca (11 mg, 47 μmol), propane-1 (12), 6,8,10-tetraen-3- yl] -2-cyclohexylpropanamide (230 mg, 0.47 mmol) , 3-yl-bis (diphenylphosphino plate) (39 mg, 0.09 mmol) , K 2 CO 3 (85 mg, 0.61 mmol), 1- a (ethenyl oxy) butane (307 ㎕, 2.36 mmol) and degassing DMF / water (3: 1, 4 ml) was added under nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 16 h and then concentrated. The residue was dissolved in EtOAc (10 mL) and rinsed with brine (10 mL). The phases were extracted with EtOAc (15 mL). Rinse the combined organic extracts were Dublin (2 x 15 mL), dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (34 mg, 16%) as a single diastereomer with undetermined stereochemistry at the quarter center.

Example 214

(2S) -3-cyclopentyl- N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-hydroxypropanamide (ABR 239994)

To a solution of (2S) -2- (acetyloxy) -3-cyclopentylpropanoic acid (available via literature method: PCT international application 2000059502) (1.00 g, 5.40 mmol) in DCM (15 mL) Chloride (732 mg, 5.77 mmol) was added followed by DMF (2 drops). The reaction was stirred for 30 min and then concentrated. The resulting residue was dissolved in DCM (3 mL) and aqueous ammonia solution (0.5 mL) was added. The reaction was concentrated and the residue was stirred in DCM (10 mL) and then filtered. The filtrate was concentrated to give (1S) -1-carbamoyl-2-cyclopentyl ethyl acetate (838 mg).

To a stirred solution of (lS) -l-carbamoyl-2-cyclopentylethyl acetate (408 mg, 2.05 mmol) in DMF (4 mL) was added methyl 3,3,3-trifluoro-2-oxopropanoate 0.34 mL, 3.4 mmol) followed by the addition of pyridine (0.18 mL, 2.2 mmol) under nitrogen. The reaction was stirred at room temperature for 1 hour. Thionyl chloride (0.16 mL, 2.2 mmol) was added at 0 &lt; 0 &gt; C. The reaction was stirred at 0 &lt; 0 &gt; C for 1 hour and then filtered through a silica short pad eluting with DCM and under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (3 mL) under nitrogen. Acyl intermediate was added to a solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (300 mg, 1.86 mmol) dissolved in DMF (5 ml) (0.30 mL, 2.2 mmol). The reaction mixture was stirred for an additional hour and then concentrated. The residue was dissolved in MeOH (10 mL) and water (5 mL). 2M NaOH _(aq) (5 mL) was added, and the resulting solution was stirred at room temperature for 1 hour. The reaction was concentrated and the residue was dissolved in EtOAc (60 mL). The organic phase was rinsed with water (3 x 20 mL) and brine (2 x 20 mL) then dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica chromatography using 0-10% MeOH as eluent and then further purified by automated reversed phase HPLC (high pH) to give the title compound as a single portion with an unidentified stereochemistry at the quarter center Obtained as a white solid as a stereoisomer (28 mg, 4%).

Example 215

(a) diastereomer 1: (2S) -2- (Cyclopentylmethoxy) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239997)

(b) Diastereomer 2: (2S) -2- (Cyclopentylmethoxy) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239998)

(2S) -2- (cyclopent-1-en-1-ylmethoxy) -N- [10,11- azatricyclo [6.4.0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] propanamide (750 mg, 1.72 mmol) and EtOH (10 mL) solution is filled The flask was evacuated and flushed with nitrogen (x 3). To the stirred solution was added dioxoplatin (39 mg, 0.17 mmol). The flask was evacuated and flushed with nitrogen (x 3) and flushed with hydrogen after exhaust (x 3). After stirring for 18 hours, the reaction was filtered through Celite ™, rinsed with EtOH and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the diastereoisomer 1 (260 mg, 35%) as a white solid as a single diastereomer with undetermined stereochemistry at the quarter center. , Diastereoisomer 2 (197 mg, 26%) as a white solid as a single diastereomer with undetermined stereochemistry at the quarter center.

Example 216

(a) Enantiomer 1: 3-Cyclopentyl- N - [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 238851)

(b) Enantiomer 2: 3-Cyclopentyl- N - [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 238856)

3-cyclopentyl- N- [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-3-yl] propanamide (40 mg, 0.11 mmol) was separated by SFC on a Chiralpak AD-H column using 23% ethanol / 77% CO ₂ as eluent. Enantiomer 1 was isolated as a white solid (15 mg, 38%). Enantiomer 2 was isolated as a white solid (13 mg, 33%).

Example 217

(a) Enantiomer 1: 3-Cyclohexyl- N - [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 238924)

(b) Enantiomer 2: 3-Cyclohexyl- N - [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 238941)

3-cyclohexyl- N- [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-3-yl] propanamide (20 mg, 0.05 mmol) was separated by SFC using 23% ethanol / 77% CO ₂ as mobile phase on a Chiralpak AD-H column. Enantiomer 1 was isolated as a brown oil (4 mg, 21%). Enantiomer 2 was isolated as a white solid (5 mg, 24%).

Example 218

(a) Enantiomer 1: 3-Cyclopentyl- N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239071)

(b) Enantiomer 2: 3-Cyclopentyl- N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239105)

3-cyclopentyl- N- [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] 12, 6,8,10- tetraen-3-yl] were separated by SFC using 15% ethanol / 85% CO ₂ as the mobile phase to propanamide (200 mg, 0.49 mmol) in a Chiralpak AD-H column . Enantiomer 1 was isolated as a white solid (77 mg, 39%). Enantiomer 2 was further purified by automated reverse phase HPLC (low pH method A) to afford the title compound as a white solid (67 mg, 34%).

Example 219

(a) Enantiomer 1: 3-Cyclopentyl- N - [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239396)

(b) Enantiomer 2: 3-Cyclopentyl- N - [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239397)

Synthesis of 3-cyclopentyl- N- [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] (12, 6,8,10-tetraen-3-yl] propanamide (120 mg, 0.27 mmol) was separated by SFC using 7% MeOH / 93% CO ₂ as mobile phase on a Chiralpak AD- Respectively. Enantiomer 1 was isolated as a white solid (46 mg, 38%). Enantiomer 2 was isolated as a white solid (46 mg, 38%).

Example 220

(a) Enantiomer 1: N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 Yl] -6 - [(2-methoxyethyl) amino] pyridine-2-carboxamide (ABR 239662)

(b) Enantiomer 2: N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 Yl] -6 - [(2-methoxyethyl) amino] pyridine-2-carboxamide (ABR 239663)

N - [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] 2-carboxamide (100 mg, 0.22 mmol) was added to a Chiralpak IC column using 12% MeOH as the mobile phase / 88% CO ₂ . Enantiomer 1 was isolated as a white solid (40 mg, 40%). Enantiomer 2 was isolated as a white solid (46 mg, 40%).

Example 221

(a) Enantiomer 1: N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (1-hydroxycyclopentyl) propanamide (ABR 239707)

(b) Enantiomer 2: N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (1-hydroxycyclopentyl) propanamide (ABR 239714)

N - [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] , 8,10- tetraen-3-yl] -3- (1-hydroxy-cyclopentyl) propanamide (125 mg, 0.29 mmol) a, with a 80% MeOH / 20% CO ₂ as the mobile phase in the column Chiralpak aS SFC. Enantiomer 1 was isolated as a white solid (44 mg, 35%). Enantiomer 2 was further purified by automated reversed-phase HPLC (low pH method A) to give the title compound as a white solid (6 mg, 4%).

Example 222

(a) Enantiomer 1: 3-Cyclopentyl- N - [9-methanesulfonyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239709)

(b) Enantiomer 2: 3-Cyclopentyl- N - [9-methanesulfonyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239710)

3-cyclopentyl- N- [9-methanesulfonyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] 12), 6,8,10- tetraen-3-yl] were separated by SFC using 80% MeOH / 20% CO ₂ for propanamide (110 mg, 0.23 mmol), as a mobile phase in a Chiralpak aS column. Enantiomer 1 was isolated as a beige solid (26 mg, 24%). Enantiomer 2 was isolated as a beige solid (34 mg, 32%).

Example 223

(a) Enantiomer 1: 3-Cyclopentyl- N - [9,10-difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239712)

(b) Enantiomer 2: 3-Cyclopentyl- N - [9,10-difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239713)

Synthesis of 3-cyclopentyl- N- [9,10-difluoro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] 1 (12), 6,8,10- tetraen-3-yl] were separated by SFC using 70% MeOH / 30% CO ₂ for propanamide (110 mg, 0.26 mmol), as a mobile phase in the column Chiralpak AD . Enantiomer 1 was isolated as a white solid (53 mg, 48%). Enantiomer 2 was isolated as a white solid (53 mg, 48%).

Example 224a

(a) Enantiomer 1: N - [9-acetyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239727)

(b) Enantiomer 2: N - [9-acetyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239728)

N - [9-acetyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] 3-yl] -3-cyclopentylpropanamide (110 mg, 0.26 mmol) was separated by SFC using 30% IPA / 70% CO ₂ as mobile phase in a Chiralpak IC column. Enantiomer 1 was isolated as a white solid (40 mg, 36%). Enantiomer 2 was isolated as a white solid (41 mg, 37%).

Example 225a

(a) Enantiomer 1: 3- (3,3-Difluoroazetidin-1-yl) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239825)

(b) Enantiomer 2: 3- (3,3-difluoroazetidin-1-yl) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239824)

3- (3,3-Difluoroazetidin-l-yl) -N- [10,11- cyclo [6.4.0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] propanamide a (116 mg, 0.27 mmol), 20% as a mobile phase in a Chiralpak IC column IPA / 80% CO ₂ . Enantiomer 1 was isolated as a white solid (35 mg, 30%). Enantiomer 2 was isolated as a white solid (37 mg, 32%).

Example 226

(a) Enantiomer 1: N - [9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239962)

(b) Enantiomer 2: N - [9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 239961)

N - [9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12) , 10-tetraen-3-yl] -3-cyclopentylpropanamide (100 mg, 0.25 mmol) was separated by SFC using 70% IPA / 30% CO ₂ as mobile phase in an Amy-C column. Enantiomer 1 was isolated as a white solid (32 mg, 32%). Enantiomer 2 was dissolved in EtOAc (2 mL) and rinsed with 0.5 M HCl _(aq) (1 mL), water (1 mL) and brine (1 mL). Concentration of the organic phase gave the title compound as a white solid (19 mg, 19%).

Example 227

(a) Enantiomer 1: 3-Cyclopentyl- N - [9- (2-methylpropanoyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239975)

(b) Enantiomer 2: 3-Cyclopentyl- N - [9- (2-methylpropanoyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239972)

To a stirred solution of N - [9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca- 2-chloro (propan-2-yl) -methanone was added at 0 &lt; 0 &gt; C under nitrogen, to a solution of the title compound of Preparation 1 (12), 6,8,10-tetraen- Magnesium / THF (655 L, 1.31 mmol) was added dropwise. Copper (I) bromide (0.6 mg, 4 μmol) was added and the reaction was then heated at 80 ° C for 15 minutes. The reaction was cooled to 0 C and quenched by the addition of water (3 mL). 1 M HCl _(aq) (3 mL) was added and the reaction was heated at 100 &lt; 0 &gt; C for 1 hour. The reaction was basified with saturated NaHCO _{3 (aq} ) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were rinsed with brine (20 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give 3-cyclopentyl- N- [9- (2- methylpropanoyl) -4-oxo-3- (trifluoromethyl) , 5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide as a racemic mixture as a yellow solid (70 mg, 36%).

3-cyclopentyl - N - [9- (2- methyl-propanoyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] (60 mg, 0.13 mmol) was treated with 30% MeOH / 70% CO ₂ as mobile phase on a Chiralpak AD-H column. SFC. Enantiomer 1 was isolated as a white solid (24 mg, 40%). Enantiomer 2 was isolated as a white solid (26 mg, 43%).

Example 228

(a) Enantiomer 1: N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-phenylpropanamide (ABR 239976)

(b) Enantiomer 2: N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-phenylpropanamide (ABR 239974)

N - [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] 3-yl] -3-phenylpropanamide (206 mg, 0.50 mmol) was treated with 75% MeOH / 25% CO ₂ as mobile phase in an Amy-C column and diethylamine Were separated by SFC. Enantiomer 1 was dissolved in EtOAc and rinsed with 1 M HCl _(aq) (2 x) and brine. The organic phase was dried (MgSO ₄ ) and concentrated to give the title product as a brown oil (75 mg, 36%). The enantiomer 2 was dissolved in EtOAc and rinsed with 1 M HCl _(aq) (2 x) and brine. The organic phase was dried (MgSO ₄ ) and concentrated to give the title product as a brown oil (88 mg, 43%).

Example 229

(a) Enantiomer 1: 3,5-Dichloro- N - [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] benzamide (ABR 239981)

(b) Enantiomer 2: 3,5-Dichloro- N - [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] benzamide (ABR 239980)

Dichloro- N- [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] 3-yl] benzamide (62 mg, 0.13 mmol) was treated with SFC using 85% MeOH / 15% CO ₂ as mobile phase on an Amy-C column Respectively. Enantiomer 1 was isolated as a white solid (20 mg, 32%). Enantiomer 2 was isolated as a white solid (22 mg, 35%).

Example 230

(a) Enantiomer 1: 3-Cyclopentyl- N - [9- (4-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239984)

(b) Enantiomer 2: 3-Cyclopentyl- N - [9- (4-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 239979)

3-cyclopentyl- N- [9- (4-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] (96 mg, 0.20 mmol) was treated with SFC using 15% MeOH / 85% CO ₂ as mobile phase on a Chiralcel 0J-H column. Lt; / RTI &gt; Enantiomer 1 was isolated as a white solid (38 mg, 40%). Enantiomer 2 was isolated as a white solid (42 mg, 44%).

Example 231

(a) Enantiomer 1: 3- (3-Cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxylic acid (ABR 240007)

(b) Enantiomer 2: 3- (3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxylic acid (ABR 240006)

(3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] , 6,8,10-tetraene-9-carboxylic acid (180 mg, 0.42 mmol) was separated by SFC using 15% MeOH / 85% CO ₂ as mobile phase in a Chiralpak AD-H column and diethylamine as the modifier. Enantiomer 1 was isolated as a white solid (70 mg, 37%). Enantiomer 2 was isolated as a white solid (60 mg, 32%).

Example 232

3-Cyclopentyl- N - {9- [4- (methylsulfanyl) phenyl] -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl} propanamide (ABR 240016)

In a sealed tube, N - [9- bromo -10,11- (trifluoromethyl) dimethyl-4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] acetamide (100 mg, 0.25 mmol) and [4- (methylsulfanyl) phenyl] boronic acid ) which was filled with _{2M Na 2 CO 3 (aq)} (326 ㎕, 0.65 mmol) and anhydrous dioxane (0.82 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (19 mg, 0.02 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 110 &lt; 0 &gt; C for 16 hours. The reaction was cooled to room temperature. 2M HCl _(aq) (2 mL) was added and the resulting mixture was stirred for 1 hour. The reaction was diluted with EtOAc. Rinse the organic phase with Dublin dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 0-5% MeOH in DCM as eluent and then further purified by automated reverse phase HPLC (low pH method A) to give the title compound as a brown solid (50 mg, 60 &lt; RTI ID = %).

Example 233

(3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxylic acid (ABR 240015)

To a solution of phenyl 11-chloro-3- (3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4 .0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-to 9-carboxylate (74 mg, 0.14 mmol) solution, under nitrogen, 2M NaOH _(aq) (343 ㎕, 0.69 mmol). The reaction was stirred at room temperature for 1 hour and then concentrated. The residue was diluted with 2M HCl _(aq) (2 mL) and extracted with EtOAc (2 x 5 mL). The combined organic extracts were rinsed with water (5 mL), dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (3 mg, 5%).

Example 234

N - [9- (4-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] butanamide (ABR 240014)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] 3-yl] butanamide (650 mg, 1.60 mmol), (4-methoxyphenyl) boronic acid (341 mg, 2.25 mmol), Na ₂ CO ₃ (680 mg, 6.42 mmol), water (2.0 mL), DME (7.0 mL) and EtOH (3.5 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (93 mg, 80 μmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 4 hours. The reaction mixture was concentrated. The residue was dissolved in EtOAc (25 mL) and rinsed with water (25 mL). The phases were extracted with EtOAc (2 x 20 mL). The combined organic extracts were rinsed with brine (30 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica chromatography and further purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (35 mg, 5%).

Example 235

2 - [(2-methoxyethyl) amino] - N - [9- (4-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -1,3-thiazole-4-carboxamide (ABR 240013)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] ), 6,8,10-tetraen-3-yl] -2 - [(2-methoxyethyl) amino] -1,3-thiazole-4-carboxamide (150 mg, 0.29 mmol) (66 mg, 0.43 mmol), Na ₂ CO ₃ (61 mg, 0.58 mmol), water (1 mL), DME (3 mL) and EtOH (2 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (17 mg, 0.01 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 16 hours. Additional (4-methoxyphenyl) boronic acid (66 mg, 0.43 mmol), Na ₂ CO ₃ (61 mg, 0.58 mmol) and Pd (PPh ₃ ) ₄ (17 mg, 0.01 mmol) were added. The solution was degassed with nitrogen and the tube sealed. The reaction was stirred at 100 &lt; 0 &gt; C for 5 hours. The reaction mixture was concentrated. The residue was dissolved in EtOAc (50 mL) and, 1M HCl _(aq) (50 mL), was rinsed with water and then dried (50 mL) and Dublin (50 mL) (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a yellow solid (39 mg, 25%).

Example 236

N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-hydroxy-1,3-thiazole- 4- carboxamide (ABR 240018)

To a stirred solution of 2-bromo-1,3-thiazole-4-carboxamide (2.93 g, 14.2 mmol) in DMF (80 mL) was added methyl 3,3,3-trifluoro- (4.42 g, 28.3 mmol) was added followed by pyridine (1.14 mL, 14.2 mmol) under nitrogen. The reaction was stirred at room temperature for 16 hours. Additional methyl 3,3,3-trifluoro-2-oxopropanoate (4.42 g, 28.3 mmol) was added and the reaction stirred for a further 4 h. Thionyl chloride (1.03 mL, 14.2 mmol) was added at 0 &lt; 0 &gt; C. The reaction was stirred at 0 &lt; 0 &gt; C for a further 2 h and then concentrated. The residue was eluted through a silica shortpot with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (10 mL) under nitrogen. Acyl intermediate was added to a solution of 4-bromo-1H-1,3-benzodiazole-2-amine (2.50 g, 11.8 mmol) dissolved in DMF (40 ml) followed by the addition of triethylamine mL, 14.2 mmol). The reaction mixture was stirred for a further 2 h and then concentrated. The residue was dissolved in EtOAc (200 mL), and then dried, rinse with 10% citric acid _(aq) (2 x 100 mL), water (2 x 100 mL) and Dublin (2 x 100 mL) (MgSO _4), filtered And concentrated. The crude product was purified by trituration in DCM to give 2-bromo- N- [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [ 6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10-tetraen-3-yl] -1,3- thiazole- 4- carboxamide and N- [9- (12), 6,8,10-tetraene-3 (12), 6,8,10-tetraene- -One] -2-chloro-1,3-thiazole-4-carboxamide (3.70 g).

Methanesulfonamide (24 mg, 0.25 mmol) was added to a suspension of NaH (60%, 11 mg, 0.27 mmol) in DMF (2 mL) at 0 <0> C under nitrogen. On the 0 ℃ stirred for 10 minutes, 2-bromo - N - [9- bromo-4-oxo-3- (trifluoromethyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^{2 , 6} ] dodeca-1 (12), 6,8,10-tetraen-3-yl] -1,3- thiazole- 4- carboxamide and N- [9- 3- (trifluoromethyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] -2 -Chloro-1,3-thiazole-4-carboxamide (100 mg) was added. The reaction was warmed to room temperature and stirred for 2 hours. Then, the temperature was raised to 80 DEG C for 4 hours. The reaction was quenched by the addition of saturated NH ₄ Cl _(aq) at 0 ° C and diluted with EtOAc (50 mL). And then drying the organic phase rinsed with water (2 x 25 mL) (MgSO 4) , filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (11 mg, 11%).

Example 237

N - [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2 - [(2-methylpropyl) amino] -1,3-thiazole-4-carboxamide (ABR 240019 )

To a stirred solution of 2-bromo-1,3-thiazole-4-carboxamide (360 mg, 1.74 mmol) in DMF (15 mL) was added methyl 3,3,3-trifluoro- (543 mg, 3.48 mmol) was added followed by the addition of pyridine (140 L, 1.74 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. Thionyl chloride (126 [mu] L, 1.74 mmol) was added at 0 [deg.] C, then the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated and the residue was filtered through a silica short pad eluting with DCM and under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (10 mL) under nitrogen. A solution of 5,6-dichloro-lH-l, 3-benzodiazol-2-amine (293 mg, 1.45 mmol) in DMF (10 mL) and triethylamine (231 L, 1.74 mmol) The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was diluted with EtOAc (50 mL) and rinsed with 10% citric acid _(aq) (2 x 25 mL), water (2 x 25 mL) and brine (2 x 25 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was triturated in DCM to give 2-bromo- N- [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4 .0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] -1,3-thiazol-4-carboxamide and 2-chloro - N - [10, Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10- Tetraen-3-yl] -1,3-thiazole-4-carboxamide (746 mg).

In a sealed tube, 2-bromo - N - [10,11- dichloro (trifluoromethyl) -4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -1,3- thiazole- 4- carboxamide and 2-chloro- N- [10,11- (12), 6,8,10-tetraen-3- (4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] (190 mg), K ₂ CO ₃ (255 mg, 1.84 mmol), anhydrous dioxane (3 mL) and 2-methylpropane-1-amine (184 [mu] L, 1.84 mmol). The tube was sealed and stirred at 130 DEG C for 1 hour. Additional K ₂ CO ₃ (255 mg, 1.84 mmol) and 2-methylpropan-1 -amine (184 μL, 1.84 mmol) were added. The reaction was stirred at 130 &lt; 0 &gt; C for a further 18 hours and then concentrated. The residue was diluted with EtOAc (30 mL) and rinsed with brine (30 mL). The phases were extracted with EtOAc (3 x 30 mL). Rinse the combined organic extracts were dried Dublin (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a brown solid (40 mg, 21%).

Example 238

3-Cyclopentyl- N - {9- [4- (dimethylamino) phenyl] -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl} propanamide (ABR 240028)

In a sealed tube, N - [9- bromo -10,11- (trifluoromethyl) dimethyl-4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] acetamide (75 mg, 0.16 mmol) and [4- (dimethylamino) phenyl] boronic acid ), 2M Na ₂ CO ₃ (326 μL, 0.65 mmol) and 1,4-dioxane (0.82 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (38 mg, 0.04 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 110 &lt; 0 &gt; C for 16 hours. The reaction was cooled to room temperature and diluted with EtOAc and 2M NaHCO3 _(aq) . Rinse the organic phase with Dublin dried (MgSO _4), filtered, and concentrated. The crude product was purified first by silica chromatography using 0-5% MeOH in DCM as eluent. It was then further purified by automated reversed-phase HPLC (low pH method A) and then purified by silica chromatography using 0-20% MeOH in DCM as eluent to give the title compound as a white solid (20 mg, 25%).

Example 239

N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2,2,2-trifluoroacetamide (ABR 240031)

To a stirred solution of trifluoroacetamide (210 mg, 1.86 mmol) in anhydrous DCM (8.3 mL) was added pyridine (120 L, 1.48 mmol) followed by methyl 3,3,3-trifluoro- Propanoate (380 [mu] L, 3.72 mmol) was added under nitrogen. The reaction was stirred at room temperature for 2 hours. Thionyl chloride (107 [mu] L, 1.48 mmol) was added at 0 [deg.] C. The reaction was stirred at 0 &lt; 0 &gt; C for 1 h and then concentrated. The residue was eluted through a silica shortpot with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (6 mL) under nitrogen. A solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (250 mg, 1.24 mmol) in DMF (2.3 mL) and triethylamine (207 L, 1.48 mmol) The reaction was stirred for 60 hours and then concentrated. The residue was dissolved in EtOAc and rinsed with brine (4 x). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 0-10% MeOH in DCM as eluent to give the title compound as a white solid (155 mg, 26%).

Example 240

N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 (12), 6,8,10-tetraen-3-yl] -2- (2-methoxyethoxy) pyridine- 4- carboxamide (ABR 240032)

To a stirred solution of 2- (2-methoxyethoxy) pyridine-4-carboxamide in anhydrous DCM (5 mL) (303 mg, 1.94 mmol) was added to a solution of methyl 3,3,3-trifluoro-2-oxopropanoate (190 mg, 0.97 mmol) . The reaction was stirred at room temperature for 2 hours. Thionyl chloride (70 [mu] L, 0.97 mmol) was added at 0 [deg.] C. The reaction was stirred at 0 &lt; 0 &gt; C for 1 hour and then filtered through a silica short pad eluting with DCM and under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (3 mL) under nitrogen. A solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (130 mg, 0.81 mmol) in DMF (2 mL) and triethylamine (136 L, 0.97 mmol) was added. The reaction was stirred for 18 h and then concentrated. The residue was diluted with EtOAc and rinsed with brine. The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was further purified by automated reverse phase HPLC (low pH method A) to afford the title compound as a white solid (10 mg, 3%) which was tritylated in MeCN and then purified by automated reverse phase HPLC.

Example 241

3-Cyclopentyl- N - [9- (4- methanesulfonylphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 240029)

To a stirred solution of 3-cyclopentyl- N- {9- [4- (methylsulfanyl) phenyl] -4-oxo-3- (trifluoromethyl) To a solution of tricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10-tetraen-3-yl} propanamide (40 mg, 80 mol) mg, 0.2 mmol) in water (1 mL). The reaction was stirred at room temperature for 2 hours, quenched with saturated Na ₂ S ₂ O _{3 (aq)} and concentrated. The resulting residue was diluted with EtOAc (15 mL) and water (10 mL). The phases were extracted with EtOAc (2 x 15 mL). The combined organic extracts were rinsed with water (20 mL), brine (40 mL) and water (2 x 10 mL). The organic phase was then dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound as a white solid (4 mg, 11%).

Example 242

N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2,2-dimethylpropanamide (ABR 240030)

To a stirred solution of 2,2-dimethylpropanamide (392 mg, 3.88 mmol) in anhydrous DCM (5 mL) under nitrogen was added methyl 3,3,3-trifluoro-2-oxopropanoate (475 μL, 4.65 mmol) followed by pyridine (313 [mu] L, 3.88 mmol). The reaction was stirred at room temperature for 16 hours. Thionyl chloride (281 [mu] L, 3.88 mmol) was added at 0 [deg.] C. The reaction was stirred at 0 &lt; 0 &gt; C for 1.5 h, then filtered through a silica shorting pad eluting with DCM and under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (5 mL) under nitrogen. Acyl intermediate was added to a solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (500 mg, 3.1 mmol) dissolved in DMF (5 ml) (516 [mu] L, 3.88 mmol). The reaction mixture was stirred for an additional hour and then concentrated. The residue was dissolved in EtOAc (20 mL) and rinsed with saturated citric acid _(aq) (30 mL). The phases were extracted with EtOAc (20 mL). Rinse the combined organic extracts with water (2 x 20 mL) and Dublin (25 mL) and then dried (MgSO _4), filtered, and concentrated. The crude product was purified by tritylation in DCM to give the title compound as a pink solid (505 mg, 61%).

Example 243

N - [9-acetyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2- (cyclopentylamino) -1,3- thiazole- 4- carboxamide (ABR 240024)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] ), 6,8,10-tetraen-3-yl] -2- (cyclopentylamino) -1,3-thiazole-4-carboxamide (150 mg, 0.26 mmol), palladium (II) acetate (21 mg, 0.05 mmol), K ₂ CO ₃ (47 mg, 0.34 mmol), 1- (ethenyloxy) butane (170 L, 1.30 mmol) and degassed DMF / water (3: 1, 4 mL) were charged under nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 20 h and then concentrated. The resulting residue was diluted with EtOAc (10 mL) and brine (10 mL). The aqueous phase was rinsed with EtOAc (15 mL) and the organic wash was discarded. Then, the extracted number to the _{IPA / CHCl 3 (2 x 25} mL). Dry the combined organic extracts (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (24 mg, 19%).

Example 244

N - [9- (3-chlorophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide (ABR 240025)

To a microwave tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] 3-yl] -3-cyclopentylpropanamide (75 mg, 0.16 mmol), (3-chlorophenyl) boronic acid (32 mg, 0.2 mmol), 2M Na ₂ CO _{3 (aq)} (0.15 mL), DME (0.80 mL) and EtOH (0.30 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (19 mg, 0.02 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred in a microwave at 120 &lt; 0 &gt; C for 1.5 h. The reaction mixture was filtered through Celite (TM) and rinsed with MeOH (30 mL). The filtrate was concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a yellow solid (35 mg, 44%).

Example 245

3-Cyclopentyl- N - [4- oxo-3- (trifluoromethyl) -9- [4- (trifluoromethyl) phenyl] -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 240022)

N - [9- (3- chlorophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca-1 (12) , 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide was used, but replacing [4- (trifluoromethyl) phenyl] boronic acid with (3- chlorophenyl) boronic acid And was used instead (47%).

Example 246

3-Cyclopentyl- N - [9- (4-fluorophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 240023)

N - [9- (3- chlorophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca-1 (12) , 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide was used, but (4-fluorophenyl) boronic acid was used in place of (3- chlorophenyl) boronic acid 29%).

Example 247

3- (3-Cyclopentylpropanamido) - N -Methanesulfonyl-10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxamide (ABR 240026)

NaH (60%, 21 mg, 0.53 mmol) was added to a stirred solution of methanesulfonamide (50 mg, 0.53 mmol) in DMF (3 mL) at 0 C under nitrogen. The reaction was stirred at 0 ° C for 30 min and then phenyl 3- A solution of DMF (2 mL) in which tricyclo [6.4.0.0 ^2,6 ] dodeca-1 (12), 6,8,10-tetraene-9-carboxylate (70 mg, 0.13 mmol) Respectively. The reaction was allowed to warm to room temperature and then heat-treated at 50 ° C for 4 hours. Saturated NH ₄ Cl _(aq) was added to the reaction, followed by quenching at 0 ° C and concentration. The resulting residue was diluted with EtOAc (50 mL) and water (25 mL). Rinse the organic layer with water (2 x 25 mL) and Dublin (2 x 25 mL) then dried (MgSO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a beige solid (30 mg, 43%).

Example 248

3-Cyclopentyl- N - [9- (methoxymethyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide (ABR 240027)

To a stirred solution of 3-cyclopentyl- N- [9- (hydroxymethyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4. 0.0 ^2,6] dodeca-1 (12), 6,8,10- tetraen-3-yl] propanamide in the (60 mg, 0.13 mmol) solution, 0 ℃, concentrated H ₂ SO ₄ (0.01 mL , 0.15 mol). The reaction was heat-treated at 50 &lt; 0 &gt; C for 24 hours. Further concentrated H ₂ SO ₄ (0.02 mL, 0.30 mol) was added at 0 ° C. The reaction was heat-treated at 60 占 폚 for 24 hours. The reaction was concentrated and the residue was dissolved in EtOAc (5 mL) and then rinsed with saturated NaHCO _{3 (aq)} (3 mL), water (3 mL) and brine (3 mL). The organic phase was dried (Na ₂ SO _4), filtered, and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (13 mg, 23%).

Example 249

tert -Butyl 3 - {[10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3- yl] carbamoyl} pyrrolidine-1-carboxylate (ABR 240049)

tert -butyl 6 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] 3-yl] carbamoyl} -2-azaspiro- [3.3] heptane-2-carboxylate was used in place of tert -butyl 3-carbamoylpiperazine Carboxylate was used in the place of tert -butyl 6-carbamoyl-2-azaspiro [3.3] heptane-2-carboxylate and 5,6-dimethyl-1H- 2-amine was used in place of 5,6-dichloro-1H-1,3-benzodiazole-2-amine. In addition, one equivalent of methyl 3,3,3-trifluoro-2-oxopropanoate was added at 2 hours after the first charge. Final purification was performed using automated reversed phase HPLC (high pH method A); (20%); m / z = 426.1 (MH-tBu) ^&lt; ⁺ & gt ^; .

Example 250

tert -Butyl 4- {[10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] carbamoyl} piperidine- 1 -carboxylate (ABR 240050)

tert -butyl 6 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] 3-yl] carbamoyl} -2-azaspiro [3.3] heptane-2-carboxylate was used in place of tert -butyl 4-carbamoylpiperidine Carboxylate was used in the place of tert -butyl 6-carbamoyl-2-azaspiro [3.3] heptane-2-carboxylate and 5,6-dimethyl-1H- benzo [d] imidazole- 2-amine was used in place of 5,6-dichloro-lH-benzo [d] imidazol-2-amine; (40%); m / z = 440.1 (M-H &^lt; ^{+ &gt;} Bu) ⁺ .

Example 251

tert -Butyl (2S) -2 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] carbamoyl} pyrrolidine- 1 -carboxylate (ABR 240051)

tert -butyl 6 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] 12), 6,8,10- tetraen-3-yl] carbamoyl} -2-aza-spiro but [3.3] using the manufacturing method of the heptane-2-carboxylate, tert - butyl (2S) -2- Carbamoylpyrrolidine-1-carboxylate was used in place of tert -butyl 6-carbamoyl-2-azaspiro [3.3] heptane-2-carboxylate; (29%); m / z = 465.8, 467.8 (M-H &^lt; ^{+ &gt;} Bu) ⁺ .

Example 252

tert -Butyl 3 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] carbamoyl} pyrrolidine- 1 -carboxylate (ABR 240052)

tert -butyl 6 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] 3-yl] carbamoyl} -2-azaspiro [3.3] heptane-2-carboxylate was used in place of tert -butyl 3-carbamoylpyrrolidine Di-1-carboxylate was used in place of tert -butyl 6-carbamoyl-2-azaspiro [3.3] heptane-2-carboxylate. Final purification was carried out by automated reversed-phase HPLC (high pH method A) to yield the title compound as a mixture of diastereomers; (32%); m / z = 466.1, 468.1 (MH-tBu) ^&lt; ⁺ & gt ^; .

Example 253

tert -Butyl 4 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] carbamoyl} piperidine- 1 -carboxylate (ABR 240053)

tert -butyl 6 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] 3-yl] carbamoyl} -2-azaspiro [3.3] heptane-2-carboxylate was used in place of tert -butyl 4-carbamoylpiperazine Piperidine-1-carboxylate was used in place of tert -butyl 6-carbamoyl-2-azaspiro [3.3] heptane-2-carboxylate; (40%); m / z = 480.1, 482.1 (MH-tBu) ^&lt; ⁺ & gt ^; .

Example 254

tert -Butyl 3 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] carbamoyl} azetidine- 1 -carboxylate (ABR 240054)

tert -butyl 6 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] 12), 6,8,10- tetraen-3-yl] carbamoyl} -2-azaspiro [3.3] heptane, but use the method of producing 2-carboxylate, tert - butyl-3-carbamoyl-azetidine -1-carboxylate was used in place of tert -butyl 6-carbamoyl-2-azaspiro [3.3] heptane-2-carboxylate; (22%); m / z = 451.8, 453.8 (MH-tBu) ^&lt; ⁺ & gt ^; .

Example 255

tert -Butyl 4 - ({[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3- yl] carbamoyl} methyl) piperidine- 1 -carboxylate (ABR 240055)

To a stirred solution of tert -butyl 4- (carbamoylmethyl) piperidine-1-carboxylate (1.00 g, 4.00 mmol) in DMF (8 mL) was added pyridine (316 L, 4.00 mmol) , 3-Trifluoro-2-oxopropanoate (104 [mu] L, 4.00 mmol) was added under argon. The reaction mixture was stirred at room temperature for 1 hour and then thionyl chloride (300 L, 4.00 mmol) was added dropwise. The reaction mixture was stirred at room temperature for a further 16 h and then concentrated to give the acylimine intermediate product. The acylimine intermediate product was dissolved in DMF (5 mL) and then 5,6-dichloro-1H-1,3-benzodiazole-2-amine (804 mg, 4.00 mmol) / DMF (7 mL) Fructylamine (0.56 mL, 4.00 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction was rinsed with brine (25 mL) and extracted with EtOAc (2 x 50 mL). Rinse by combining the organic phase with water, dry (Na ₂ SO _4), filtered, and concentrated. The crude product was purified by silica chromatography using 2% MeOH in DCM as eluent to afford the title compound as a red solid (65 mg, 6%); m / z = 450.4, 452.4 (MH-CO ₂ tBu) ⁺ .

Example 256

tert -Butyl 2- (2- {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3- yl] carbamoyl} ethyl) piperidine- 1 -carboxylate (ABR 240056)

tert -butyl 4 - ({[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] 12, 6,8,10- tetraen-3-yl] carbamoyl} methyl) piperidine, but using the method of producing 1-carboxylate, with the proviso that tert-butyl 2- (2-carbamoyl Ethyl) piperidine-1-carboxylate was used in place of tert -butyl 4- (carbamoyl-methyl) piperidine-1-carboxylate (17%); m / z = 463.4, 465.4 (MH-CO ₂ ^t Bu) ⁺ .

Example 257

tert- Butyl 3 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3- yl] carbamoyl} -3-fluoroazetidine- 1 -carboxylate (ABR 240057)

Pyridine (105 L, 1.30 mmol) was added to a stirred solution of tert- butyl 3-carbamoyl-3-fluoroazetidine-1-carboxylate (285 mg, 1.30 mmol) in DMF (25 mL) Methyl 3,3,3-trifluoro-2-oxopropanoate (407 mg, 2.61 mmol) was added under nitrogen. The reaction was stirred at room temperature for 2 hours. Thionyl chloride (95 L, 1.30 mmol) was added at 0 &lt; 0 &gt; C. The reaction was stirred at 0 &lt; 0 &gt; C for 1 h and then concentrated. The residue was eluted through a silica shortpot with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (10 mL) under nitrogen. A solution of 5,6-dichloro-lH-l, 3-benzodiazole-2-amine (220 mg, 1.08 mmol) in DMF (10 mL) and triethylamine (182 L, 1.30 mmol) was added. The reaction was stirred for 2 hours and then concentrated. The residue was dissolved in EtOAc (50 mL) and rinsed with water (4 x 50 mL) and brine (3 x 50 mL). The organic phase was dried (Na ₂ SO _4), filtered, and concentrated. Purification of the product by automated reverse phase HPLC (low pH method A) afforded the title compound as a yellow solid (59 mg, 10%); m / z = 469.8, 471.8 (MH &^lt; ^{+ &} gt ^; = Bu) ⁺

Example 258

Methyl 3- [3- (3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-9-yl] benzoate (ABR 240058)

To a sealed tube was added N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] 3-yl] -3-cyclopentylpropanamide (100 mg, 0.22 mmol) and [3- (methoxycarbonyl) phenyl] boronic acid (49 mg, 0.27 mmol) , Na ₂ CO ₃ (42 mg, 0.39 mmol), water (0.20 mL), DME (3.00 mL) and EtOH (1.25 mL). The solution was degassed with nitrogen. Pd (PPh ₃₎ was added ₄ (25 mg, 0.02 mmol) and the solution was sealed tube was degassed with nitrogen. The reaction was stirred at 100 &lt; 0 &gt; C for 18 hours. The reaction mixture was filtered through Celite (TM), rinsed with MeOH (30 mL), and the filtrate was concentrated. The resulting residue was dissolved in EtOAc (20 mL), rinsed with water (30 mL), saturated citric acid _(aq) (30 mL) and brine (30 mL), dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by silica chromatography using 0-100% EtOAc in heptane as eluent and 0-10% MeOH in DCM then to give the title compound as a brown solid (50 mg, 30%); m / z = 515.3 (MH) ^&lt; ⁺ & gt ^; .

Example 259

N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] acetamide (ABR 238786)

Methyl 3,3,3-trifluoro-2-oxopropanoate (678 mg, 4.34 mmol) was added to a solution of acetamide (220 mg, 3.72 mmol) in DMF (50 mL) , 3.72 mmol) was added under nitrogen. The reaction was stirred at room temperature for 2 hours. Thionyl chloride (270 [mu] L, 3.72 mmol) was added at 0 [deg.] C. The reaction was stirred at 0 &lt; 0 &gt; C for 1 h and then concentrated. The residue was eluted through a silica shortpot with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (25 mL) under nitrogen. Acyl intermediate was added to a solution of 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (0.50 g, 3.1 mmol) dissolved in DMF (25 ml) Amine (519 [mu] L, 3.72 mmol). The reaction mixture was stirred for an additional 16 hours and then concentrated. The residue was dissolved in EtOAc (100 mL), and then dried, rinse with 10% citric acid _(aq) (3 x 50 mL), water (3 x 50 mL) and Dublin (3 x 50 mL) (MgSO _4), filtered And concentrated. The crude product was purified by tritylation in DCM to give the title compound as a white solid (182 mg, 18%); m / z = 327.0 (MH) ^&lt; ⁺ & gt ^; .

Example 260

N - [9-bromo-10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] acetamide (ABR 240059)

DCM (25 mL) was stirred while a N - [10,11-dimethyl (trifluoromethyl) -4-oxo-3--2,5,7- triaza-tricyclo [6.4.0.0 ^2,6] dodeca (12 mg) was added NBS (82 mg, 0.46 mmol) to a solution of 6-chloro-car-1 (12), 6,8,10-tetraen-3-yl] acetamide (150 mg, 0.46 mmol). First, the reaction was stirred at room temperature for 3 hours. The reaction was then stirred for an additional 20 hours. During this period, additional NBS (164 mg, 0.92 mmol) was added in portions. The reaction was then concentrated. The residue was dissolved in EtOAc (50 mL) and rinsed with water (2 x 50 mL) and brine (50 mL). The organic phase was dried (MgSO _4), filtered, and concentrated. The crude product was triturated in DCM to give the title compound as a yellow solid (122 mg, 66%); m / z = 404.8, 406.8 (MH) ^&lt; ⁺ & gt ^; .

Example 261

N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2 - [(2- methoxyethyl) amino] pyrimidine- 4- carboxamide (ABR 239626)

To a solution of 2-chloropyrimidine-4-carboxamide (available via literature method: PCT International Application 2001068612) (330 mg, 2.08 mmol) in DMF (6 mL) was added methyl 3,3,3-tri Fluoro-2-oxopropanoate (355 [mu] L, 3.47 mmol) was added followed by pyridine (170 [mu] L, 2.08 mmol) under nitrogen. The reaction was stirred at room temperature for 2 hours. Thionyl chloride (150 [mu] L, 2.08 mmol) was added at 0 [deg.] C. The reaction was stirred at 0 &lt; 0 &gt; C for 1 h and then concentrated. The residue was eluted through a silica shortpot with DCM and filtered under nitrogen. The filtrate was concentrated and the remaining acyl intermediate was dissolved in DMF (5 mL) under nitrogen. Acyl intermediate was added to a solution of DMF (8 ml) in which 5,6-dimethyl-1H-1,3-benzodiazole-2-amine (280 mg, 1.74 mmol) was dissolved, Amine (280 [mu] L, 2.08 mmol). The reaction mixture was stirred for an additional 16 hours and then concentrated. The residue was dissolved in EtOAc (50 mL), rinsed with water (3 x 50 mL) and brine (2 x 50 mL), dried (MgSO ₄ ), filtered and concentrated to give 2-chloro-N- [ Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.02,6] dodeca-1 (12), 6,8,10 -Tetraen-3-yl] pyrimidine-4-carboxamide. (260 mg, 15%). m / z = 424.95 (MH) &lt; + &gt;.

To a sealed tube was added 2-chloro-N- [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.02,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] pyrimidine-4-carboxamide (250 mg, 0.35 mmol), 2-methoxyethan- the _{㎕, 1.06 mmol), K 2} CO 3 (150 mg, 1.06 mmol) and DMF (5 mL) were charged. The tube was flushed with nitrogen, sealed and then stirred at 100 &lt; 0 &gt; C for 6 hours. The reaction mixture was then concentrated and the resulting residue was diluted with EtOAc (20 mL) and water (20 mL). The phases were extracted with EtOAc (2 x 10 mL). The combined organic extracts were rinsed with 10% citric acid (aq) (2 x 20 mL) and brine (20 mL), then dried (MgSO4), filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH method A) to give the title compound as a white solid (50 mg, 31%).

The compound structures of the above examples are shown in Table 1.

Table 1

NMR and mass spectral data for the examples of the present invention are shown in Table 2 .

Table 2

Biological analysis

S100A9 Biological reagents prepared and purified for relevant assays

Recombinant human S100A9 wild type

Cultivation : Expression of rhS100A9 wt was achieved by stirring in a flask while inducing the working cell bank BL21 (DE3) / pET1120 (pLR757) to 0.25 mM IPTG. The cell pellet was frozen.

Purification of inclusion bodies : The E. coli pellet was thawed at RT by the addition of 150 mL cell lysis buffer (50 mM Tris / HCl, 1 mM EDTA, 25% Saccarose, pH 8.0) and sonicated in ice in a beaker at 3 x 15 s Respectively. Thereafter, 10 μl / mL pellet solution of 1 M MgCl ₂ (10 mM final concentration), 1 μl 1 M MnCl ₂ (1 mM final concentration) / mL pellet solution and 1 μl 10 mg / mL DNase I Final concentration) / mL Pellet solution was added. (20 mM Tris / HCl, pH 7.5, 2 mM EDTA, 1% Nonidet P-40) was incubated with protease inhibitor (complete miniprotease inhibitor, Roche), 1-2 tablets / 25 mL in a volume ratio of 1: 1. The solution was centrifuged at 14,000 xg at 5 [deg.] C for 20 minutes. The pellet was resuspended in 90 mL of 0.5% Triton X-100, 1 mM EDTA, sonicated at 3 x 15 s and spun down again. This washing and sonication procedure was repeated five more times.

Resuspension and folding : Milli-Q water was used for all solutions and dialysis steps. The final pellets were 8 M urea, 40 mM DTT is added to the buffer solution 500 mM NaH ₂ PO _4, pH 1.8 was resuspended in 100 mL. When the solution became clear, it was centrifuged at 20,000 x g for 5 minutes at 5 [deg.] C for 25 minutes. The supernatant containing the resuspended inclusion bodies was titrated to pH 2 using 500 mM phosphate buffer, pH 1.8.

1st dialysis of the supernatant was carried out for 6 hours in a 5 L 50 mM NaH ₂ PO ₄ buffer, 1.5 mM DTT, pH 2. Secondary dialysis was carried out in 5 L of 10 mM Na-acetate buffer, 150 mM NaCl, 1.5 mM DTT, pH 4 for 15 hours. Tertiary dialysis was performed in 5 L of 10 mM Na-acetate buffer, 150 mM NaCl, 1.5 mM DTT, pH 4 for 8 hours. Quadrature dialysis was performed in 5 L of 20 mM Tris / HCl, 150 mM NaCl, 1.5 mM DTT, pH 7.2 for 16 hours. Fifth dialysis was performed in 5 L of 20 mM Tris / HCl, 1 mM EDTA, 1 mM EGTA, 1.5 mM DTT, pH 8.5 for 6 hours. Centrifugation was carried out at 22,000 x g for 30 minutes at 5 &lt; 0 &gt; C.

Purification by Chromatography: All chromatographic columns and resin were purchased from GE HealtCare of Sweden. DTT was added at a final concentration of 1.5 mM. Anion exchange chromatography performed on the HiPrep Q FF 16/10 column was carried out at a flow rate of 1.5 mL / min and 0-1 M NaCl in 20 mM Tris, 1 mM EDTA, 1 mM EGTA, 1.5 mM DTT, pH 8.5 Concentration gradient. The same buffer with no added NaCl was used for equilibration and washing prior to elution. The fractions containing rhS100A9wt were pooled and concentrated to 1.5 mL using Centriprep YM-3 (Amicon, USA).

Size exclusion chromatography performed on a Superdex 75 16/790 column was performed using HBS-N buffer (10 mM Hepes, 150 mM NaCl, pH 7.4) supplemented with 10 mM DTT at a flow rate of 0.5 mL / min. The PD-10 was run for buffer exchange with 10 mM Hepes, 150 mM NaCl, pH 7.5.

Biacore binding assay

S100A9 and its estimated target receptors - eg, Ca2 ⁺ and Zn2 ⁺ -dependent interactions of RAGE and TLR4 - were studied by surface plasmon resonance (SPR) techniques (Bjork et al. 2009). Briefly, S100A9 was injected onto RAGE and TLR4 immobilized via primary amine on a via core sensor chip under conditions where Ca ²⁺ and Zn ²⁺ were present at physiological concentrations, Intelligent real - time analysis. It is obvious that this analysis can be done in the opposite manner, in which S100A9 is fixed and RAGE and TLR4 are injected. In Figure 1 , an inhibition effect assay for the interaction between S100A9 and RAGE is illustrated - this assay is described in detail below. One of ordinary skill in the art will be able to perform essentially the same analysis for the interaction between S100A9 and TLR4.

In this assay, the inhibitory effects of the compounds of the present invention investigated for protein-protein interactions between S100A9 and RAGE or TLR4, respectively, were confirmed. Also reference to Fig.

Inhibition assay, biot-hS100A9: hRAGE-Fc

principle. AlphaScreen (Amplified Luminescent Proximity Homogeneous Assay) contains two types of beads, alpha donor beads and acceptor beads (PerkinElmer). When the laser is excited at 680 nm, the photosensitizer of the donor bead converts ambient oxygen to a more excited singlet state. The singlet oxygen molecule diffuses (up to 200 nm) and reacts with the thiocene derivative of the acceptor bead to generate a luminescent reaction. The fluorescence end of the acceptor bead then emits light at 520-620 nm, which can be detected with the EnVision® multi-label plate reader (PerkinElmer). Beads are light-sensitive, and all work with beads is performed under a green light filter (Roscolux Chroma Green # 389, Rosco) or under subdued light conditions.

In the AlphaScreen inhibition assay described herein, protein A (Staphylococcus aureus) conjugated to the acceptor beads is used with donor bead (Perkin Elmer 6760617M) coated with streptavidin. The acceptor beads are pre-incubated with Fc-tagged recombinant human RAGE (rhRAGE-Fc) to allow binding of rhRAGE-Fc to protein A on the bead. Biotinylated human S100A9 (biot-hS100A9) is pre-incubated with a low molecular weight test compound. The pre-mix is then placed in the wells of the microplate and incubated for interaction between biot-hS100A9 and rhRAGE-Fc. Subsequently, donor beads coated with streptavidin are added to allow streptavidin to bind to biotinylated hS100A9. After further incubation, measure the signal.

If no inhibitor compound is added, the interaction of biot-hS100A9 with rhRAGE-Fc will place the acceptor and donor bead adjacent, resulting in a strong signal. If an inhibitor is added, the complex will not form and thus the signal will be reduced.

Compounds and reagents.

AlphaScreen® General IgG (Protein A) Detection Kit, (PerkinElmer 6760617M)

HBS-P buffer (GE Healthcare, BR-1003-68)

HBS-N buffer (GE Healthcare, BR-1003-69)

CaCl ₂ / HBS-P

ZnCl ₂ / Milli-Q water

DMSO

Biotinylated hS100A9 (EZ-link IA-PEG2-biotin reagent, Pierce Biotechnology) / HBS-N

rhRAGE-Fc (R & D Systems, 1145-RG-50) / HBS-N

fair. The AlphaScreen assay method is used to screen the inhibitory effect of various compound samples at fixed concentrations or to measure the IC50 while modifying the compound concentration. A sample of the test compound and the reference material are prepared as a solution in DMSO. The reference substance inhibitor and DMSO are used as the inhibition and non-inhibition control groups respectively defined in the assay. The percent inhibition of the test compound and the reference material in the assay is calculated by comparing the obtained assay signal to the signal value of the DMSO single control (no compound).

The assay concentrations of biotinylated hS100A9 and rhRAGE-Fc were batch dependent and were determined by individual cross-tight experiments using these AlphaScreen inhibition methods to verify optimal set-up for signal strength and achievement of the indicated inhibition using the reference compound Measured and determined. The final assay concentration of the acceptor bead or donor bead is 20 占 퐂 / mL.

Experimental set-up for screening and preparation of solutions and beads

The assay buffers are prepared by adding CaCl ₂ and ZnCl ₂ to HBS-P and prepared freshly in the experiment.

- Biotin-hS100A9 solution for the experiment is prepared by diluting an appropriate amount of biot-hS100A9 stock solution in assay buffer (+ CaCl ₂ and ZnCl ₂ ) and incubating at room temperature for 30 min.

- Prepare the experimental rhRAGE-Fc solution by diluting an appropriate amount of rhRAGE-Fc stock in assay buffer.

- Protein A acceptor beads are diluted in assay buffer and then added in equal volume to the prepared rhRAGE-Fc diluent. Beads are photosensitivity. Cover the vial with aluminum foil and incubate at room temperature under dark conditions until the incubation of the biot-hS100A9 + compound is complete (see below).

Streptavidin-coated donor beads are diluted in assay buffer. Beads are very sensitive to light. Cover the vial with aluminum foil and incubate at room temperature under dark conditions until used (see below).

Sample dilution and incubation with biot-hS100A9

- Dilute a sample of test compound, titration reference and DMSO control in assay buffer.

- The diluted test compound, reference material and DMSO control are placed in wells of a Greiner microtiter 96 well plate (PP, u-shaped bottom (no. 650201)) and a biot-hS100A9 dilution is added in each well to the sample (Final concentration of DMSO ≤1.25% (v / v)). Plates are covered with a plate and incubated for 1 hour at room temperature on an Orbital Plate Stirrer under dark conditions.

Incubation of biot-hS100A9 + compound samples and rhRAGE-Fc-acceptor beads in Optiplate

After biot-hS100A9 + compound incubation, transfer the solution to the Optiplate (Optiplate 384 white, Perkin Elmer no. 6007299) and add the rhRAGE-Fc-acceptor bead solution to each well (using light filtered with a green filter) . Plates are covered with a plate and incubated in the plate under dark conditions at 25 DEG C nominally for 40 minutes.

Incubation of the biot-hS100A9 + compound sample and the rhRAGE-Fc-acceptor and donor beads on the optiplate

After incubation, donor bead solution is added to each well (using light filtered with a green filter). Plates are covered with a plate and incubated in the plate under nominally dark &lt; RTI ID = 0.0 &gt; 25 C &lt; / RTI &gt; After 50 minutes, the plates are incubated (under dark conditions) in a side-by-side laboratory bench of the EnVision (R) apparatus for temperature equilibration for 10 minutes.

Reading Optiplate from EnVision® Multi-Label Plate Reader

- Remove the plate seal and place the plate in EnVision® for 5 minutes and read.

Calculation. The percent inhibition of each sample (test compound or reference material) is calculated by the formula: 1- (signal of sample / signal of DMSO) x 100%.

The IC50 values of the compounds of the present invention in the S100A9-RAGE inhibition assay are shown in Table 3.

Table 3

Cytotoxicity analysis

principle. Through the analysis described in this method, direct toxicity (24 hour incubation) and anti-proliferative effect (72 hours incubation) are investigated. Various concentrations of the test compound are incubated with the cells, and then the cell growth reagent is added. The formation of formazan produced by metabolically active cells is then measured by a spectrophotometer.

Compounds and reagents. Jurkat cells, DMSO, cell proliferation reagent (Roche Ref no. 11644807001).

solution. R10 medium = RPMI 1640 medium + 10% fetal bovine serum, 5% Na-pyruvate, Lonza, Belgium. Tripplane blue solution 0.4%, Sigma. DMSO stock solution of the test compound. A positive control DMSO stock solution for anti-proliferation. A negative control DMSO stock solution.

fair. Transfer Jurkat cells to a 50 mL test tube. Dilute with a small amount of trypan blue solution and count the cells. The cell concentration is adjusted to a final concentration of 0.2 x ¹⁰⁶ cells / mL. Cells are inoculated into 96-well flat-bottomed sterile plates (10,000 cells / well) by injecting cell suspensions into all but the wells to which R10 is added and the wells to which no cells are added (blank).

Stock solutions are serially diluted in 96-well plates at concentrations ranging from 0.070 to 25 mM. Solutions of DMSO dilution plates are further diluted with R10 medium to make concentrations at 0.28-200 μM intervals.

The solution of the R10 dilution plate is added to the wells of the cell-inoculated plate, but the wells with only R10 are excluded. The final concentration of compound is 0.14-100 μM, and the final concentration of DMSO in the culture plate is 0.2%, which is considered to have no significant effect on cell proliferation. Two identical plates are prepared, one is incubated for 24 hours and the other is incubated for 72 hours. The plates are incubated under conditions of 37 ° C, 5% CO ₂ and 90% Rh.

Measure. 24 hours of incubation, the cell proliferation reagent was added to 10 ㎕ / well of one of two identical plates and these are incubated the plate again (37 ℃, 5% CO ₂ and 90% Rh). After incubation for 2 hours, absorbance is measured at 450 nm in a spectrophotometer. This procedure is repeated for another plate incubated for 72 hours.

Calculation. Calculate the values in the background. The absorbance measured at each concentration, including the control (cell wells and compound-free addition wells), is corrected in the background. Divide the calibrated absorbance value at each concentration by the calibrated absorbance of the control group, and plot the "% for control" value against the concentration. Then, IC50 is calculated.

In vivo model MC38 / mouse.

Female C57B1 / 6 mice approximately 7 weeks old were purchased. Prior to beginning the experiment, the mice were adapted to the laboratory for a week or more. Mice were generally used at the age of 8-12 weeks. In all experiments, control mice were randomly selected. The control group was treated the same as the treatment group, but no drug compound was administered. Tumor disease was caused by subcutaneous injection of approximately 500,000 MC38-C215 cells into 100 μl of Matrigel (Day 0). This cell line was cultured in R10 medium (RPMI-1640 + ultra glutamine + 10% fetal bovine serum, 50 μM beta-mercaptoethanol and 0.5 mg / ml G418 sulfate) as C215-transfected murine MC38 colorectal adenocarcinoma. From day 7, tumor growth was measured using a caliper three times per week and the tumor volume was calculated. The tumor volume is calculated as V = L x W ² x 0.4 where V is volume (mm ² ), L is length (mm), W is width (mm) and L> W or L = W (Attia 1966) to be. When the tumors of the control group reached the appropriate size, the experiment was terminated and the mice were euthanized (usually 12-16 days) and tumors were harvested and weighed. Using the compound in Example 218a in Figure 3 shows the results obtained.

Abbreviations Used

aq Mercury

CHRM Cryopreserved hepatocyte recovery medium

DCE 1,2-Dichloroethane

DCM Dichloromethane

DME Dimethoxyethane

DMF N, N -dimethylformamide

DMSO Dimethyl sulfoxide

DMPU 1,3-dimethyltetrahydropyrimidin-2 (1H) -one

dppf 1,1'-bis (diphenylphosphanyl) ferrocene

DTT Daithiotraceol

EDC.HCl N- [3- (dimethylamino) propyl] - N '- ethylcarbodiimide

             Hydrochloride (1: 1)

EDTA Ethylenediaminetetraacetic acid

EGTA Ethylene glycol tetraacetic acid

EtOAc Ethyl acetate

EtOH ethanol

FACS Fluorescence-activated cell sorting

h Time (s)

HPLC High Performance Liquid Chromatography

IPA Propan-2-ol

IPTG Isopropyl beta-D-1-thiogalactopyranoside

KHB Krabs-Hensel Height Bicarbonate Buffer

MeCN Acetonitrile

MeOH Methanol

min Minute (s)

NaHMDS Sodium bis (trimethylsilyl) amide

NBS 1-Bromo-2,5-pyrrolidinedione

NMP 1-methylpyrrolidin-2-one

Ph Phenyl

NMR Nuclear magnetic resonance

PBS Phosphate buffered saline

PBST Phosphate buffered saline Tween-20

RT Room temperature

SCX Strong cation exchange

SFC Supercritical fluid chromatography

SPhos Dicyclohexyl (2 ', 6 ' -dimethoxybiphenyl-2-yl)

tBu tert-butyl

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin film chromatography

wt weight

Claims (15)

A compound of formula (I) or a pharmaceutically acceptable salt thereof:

In this formula,
R _A, R _B and R _C are independently H, halogen, cyano, R ₁ O, R ₁ O optionally substituted C1-C6 optionally substituted alkyl, R ₁ O C3-C6-cycloalkyl, R _{2 C (O), R 3} S, R 4 S (O) 2, R 5 OC (O), (R 6 ON) C (R 7), R 8 R 9 NC (O), R 10 R 11 N _{a, R 12 S (O) 2} NR 13, R 14 S (O) 2 NR 15 C (O), optionally substituted with one or more R ₁₆ moiety is phenyl, and one or more R ₁₆ moiety is an optionally substituted C 5- or 6-membered heterocyclyl, or
One of R _A and R _C together with R _B forms a bi-radical - (CH ₂ ) _m - wherein m is an integer from 3 to 5 and the other of R _A and R _C is H, halogen, cyano, R ₁ O, R ₁ O optionally substituted C1-C6 alkyl, optionally substituted C3-C6-cycloalkyl in _{R 1 O, R 2 C (} O), R 3 S, R 4 S (O) 2, R 5 _{OC (O), (R 6} ON) C (R 7), R 8 R 9 NC (O), R 10 R 11 N, R 12 S (O) 2 NR 13, R 14 S (O) 2 NR 15 C (O), selected from one or more of R ₁₆ is optionally substituted with a phenyl moiety, and one or more R ₁₆ moiety in an optionally substituted 5-or 6-immunogenic and heterocyclyl;
Each R ₁₆ is independently halogen, cyano, nitro, R ₁₇ O, R ₁₇ O in an optionally substituted C1-C6 alkyl, R ₁₇ O in an optionally substituted C3-C6-cycloalkyl, R ₁₈ C (O _{), R 19 S, R 20} S (O) 2, R 21 OC (O), (R 22 ON) C (R 23), R 24 R 25 NC (O), R 26 R 27 N, R 28 S (O) ₂ NR ₂₉ , and R ₃₀ S (O) ₂ NR ₃₁ C (O);
Each R ₁ -R ₃₁ is independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl;
W is a direct bond or X ₁ -X ₂ -X ₃ ;
X ₁ is C ₁ -C 2 alkylene and C ₁ -C 2 alkylene is optionally substituted with C 1 -C 4 alkyl or R ₃₂ O;
X ₂ is O or is omitted;
X ₃ is a direct bond or C 1 -C 2 alkylene, and C 1 -C 2 alkylene is optionally substituted with C 1 -C 4 alkyl or R ₃₂ O;
R ₃₂ is selected from H and C 1 -C 4 alkyl;
R _D is C 1 -C 6 alkyl or a cyclic moiety selected from phenyl, 4- to 6-membered heterocyclyl and C 4 -C 6 cycloalkyl, wherein said cyclic moiety is optionally substituted with one or more R ₃₃ Substituted;
Each R ₃₃ is independently selected from the group consisting of halogen, cyano, C 1 -C 6 alkyl optionally substituted with R ₃₄ O, C 3 -C 6 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl, R ₃₄ O, R ₃₅ OC (O), R ₃₆ S (O) ₂ , R ₃₇ C (O), R ₃₈ R ₃₉ N, R ₄₀ R ₄₁ N (CO) Or two R &lt; ₃₃ &gt; groups bonded to one and the same carbon atom may form a 4- to 6-membered ring optionally containing one or more heteroatoms in the ring together with the carbon atom to which they are attached;
R ₃₄ is independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted with R ₄₂ O;
Each R ₃₅ -R ₃₆ is independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl;
R ₃₇ is independently selected from C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted with R ₄₃ O;
R ₃₈ and R ₃₉ are independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted by R ₄₄ R ₄₅ N or R ₄₆ O, or
R ₃₈ and R ₃₉ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring optionally containing one or more other heteroatoms and optionally substituted with C 1 -C 6 alkyl;
R ₄₀ and R ₄₁ are independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted with R ₄₇ R ₄₈ N or R ₄₉ O, or
R ₄₀ and R ₄₁ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring optionally containing one or more other heteroatoms and optionally substituted by C 1 -C 6 alkyl;
R ₄₄ and R ₄₅ are independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, or
R ₄₄ and R ₄₅ together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring optionally containing one or more other heteroatoms and optionally substituted by C 1 -C 6 alkyl ;
R ₄₇ and R ₄₈ are independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, or
R ₄₇ and R ₄₈ together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring optionally containing one or more other heteroatoms and optionally substituted by C 1 -C 6 alkyl ;
R ₄₂ , R ₄₃ , R ₄₆ and R ₄₉ are independently selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl;
Wherein any alkyl is optionally substituted with one or more F. The method according to claim 1,
Wherein R _D is a cyclic moiety selected from phenyl, 4- to 6-membered heterocyclyl and C 4 -C 6 cycloalkyl, wherein said cyclic moiety is optionally substituted with one or more R ₃₃ , Acceptable salt. 3. The method according to claim 1 or 2,
Wherein R _D is a cyclic moiety selected from 4- to 6-membered heterocyclyl, wherein said cyclic moiety is optionally substituted with one or more R _{33 s} or a pharmaceutically acceptable salt thereof. 4. The method according to any one of claims 1 to 3,
Wherein R _D is a cyclic moiety selected from 5- to 6-membered heteroaryl, wherein said cyclic moiety is optionally substituted by one or more R _{33 s} or a pharmaceutically acceptable salt thereof. 3. The method according to claim 1 or 2,
Wherein R _D is a cyclic moiety selected from C 4 -C 6 cycloalkyl, wherein said cyclic moiety is optionally substituted with one or more R ₃₃ ; or a pharmaceutically acceptable salt thereof. 3. The method according to claim 1 or 2,
Wherein R &lt; _D &gt; is phenyl optionally substituted by one or more R &lt; _{33 &} gt ;. 7. The method according to any one of claims 1 to 6,
R _A , R _B, and R _C are independently selected from H, halogen, C 1 -C 4 alkyl, and R ₂ C (O), or a pharmaceutically acceptable salt thereof. 7. The method according to any one of claims 1 to 6,
R _A, R _B and R _C has one of the one or more R ₁₆ moiety is an optionally substituted phenyl or optionally substituted 5-or 6-immunogenic heterocyclyl with one or more R ₁₆ moiety, R _A, R _B and R _C of the other two are independently selected from H, halogen and C1-C4, a compound or pharmaceutically acceptable salt thereof, chemical selected from alkyl. 9. The method according to any one of claims 1 to 8,
And W is a direct bond, or a pharmaceutically acceptable salt thereof. 9. The method according to any one of claims 1 to 8,
W is X1-X2-X3, or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 selected from the following compounds or pharmaceutically acceptable salts thereof:
6-chloro -N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -pyridine-2-carboxamide;
N - [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -6-fluoropyridine-2-carboxamide;
N- [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -benzamide;
2-Cyclohexyl- N- [4-oxo-3- (trifluoromethyl) -2,5,7-tri-azatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -acetamide;
3- (Morpholin-4-yl) - N- [4-oxo-3- (trifluoromethyl) -2,5,7-tri-azatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -propanamide;
N- [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (pyrrolidin-1-yl) propanamide;
3- (oxan-4-yl) - N- [4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -propanamide;
2-bromo -N- [3-Oxo-4- (tri-fluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-4-yl] -benzamide;
3-Cyclopentyl -N- [4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -propanamide;
3,5-dimethoxy -N- [3-Oxo-4- (trifluoromethyl) -2,5,7-tri-azatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-4-yl] -benzamide;
6-methyl -N- [3-Oxo-4- (tri-fluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-4-yl] -pyridine-3-carboxamide;
3,5-dichloro -N- [4-oxo-3- (tri-fluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -benzamide;
3-cyclohexyl -N- [3-Oxo-4- (trifluoromethyl) -2,5,7-tri-azatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-4-yl] -propanamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-tri-azatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -benzamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-tri-azatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3-phenylpropanamide;
3- (2-Chlorophenyl) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -propanamide;
3,5-Dichloro- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] benzamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-tri-azatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -4-phenylbenzamide;
4-Cyclopentyl- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -butanamide;
2-Cyclohexyl- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -acetamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6- (2,2,2-trifluoroethoxy) -pyridine-3-carboxamide;
1-cyclopentanecarbonyl- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -pyrrolidine-3-carboxamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (morpholin-4-yl) propanamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -pyrrolidine-3-carboxamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -piperidine-4-carboxamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -1- (2-methoxyacetyl) -piperidine-4-carboxamide;
3-Cyclopentyl -N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -propanamide;
6-chloro -N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -pyridine-3-carboxamide;
3- (2,6-dichlorophenyl) -N- [10,11-Dimethyl-4-oxo-3- (tri- fluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -propanamide;
2-bromo -N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -benzamide;
6- (cyclohexylamino) -N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-tri-azatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -pyridine-3-carboxamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -6-methylpyridine-3-carboxamide;
3-Cyclohexyl- N - [10,11-dimethyl-3-oxo-4- (trifluoromethyl) -2,5,7- triazatricyclo- [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-4-yl] -propanamide;
N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (pyridin-3-yl) propanamide;
6- (cyclohexylamino) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-tri-azatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] pyridine-2-carboxamide;
6-Cyclohexyl- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -pyridine-2-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3-phenylpropanamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -benzamide;
3-Cyclopentyl- N- [10,11-di-chloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -propanamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-azaspiro [3.3] heptane-6-carboxamide;
(2S) - N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] pyrrolidine-2-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-tri-azatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -pyrrolidine-3-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-tri-azatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -piperidine-4-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-tri-azatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -1- (2-methoxyacetyl) -piperidine-4-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -1- (3-methylbutanoyl) -piperidine-4-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -1- (3,3,3-trifluoropropanoyl) -piperidine-4-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -azetidine-3-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -1- (ethanesulfonyl) azetidine-3-carboxamide;
1-acetyl- N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -azetidine-3-carboxamide;
1-cyclopentanecarbonyl- N- [10,11-Dichloro-4-oxo-3- (tri- fluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -pyrrolidine-3-carboxamide;
(3R) -1- (Cyclopentane-sulfonyl) - N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -pyrrolidine-3-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-tri-azatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -1- (pyridin-2-yl) azetidine-3-carboxamide;
3-Cyclohexyl- N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -propanamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-tri-azatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -cyclopentanecarboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-tri-azatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -cyclohexanecarboxamide;
3-Chloro- N - [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -benzamide;
3,5-Dichloro- N - [10,11-di-chloro-4-oxo-3- (trifluoro-methyl) -2,5,7- triaza- tricyclo [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -benzamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -4- (pyrrolidin-1-yl) butanamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -4- (morpholin-4-yl) butanamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2- (morpholin-4-yl) acetamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (morpholin-4-yl) propanamide;
6-Chloro- N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -pyridine-2-carboxamide;
6- (Azetidin-l-yl) - N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -pyridine-2-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -6- (2,2,2-trifluoroethoxy) -pyridine-2-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -6- (dimethylamino) pyridine-2-carboxamide;
6- (cyclohexylamino) - N - [10,11-dichloro-4-oxo-3- (tri- fluoromethyl) -2,5,7- triaza- tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -pyridine-2-carboxamide;
N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza- tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -6- (ethylamino) pyridine-2-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2- (piperidin-4-yl) acetamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (piperidin-2-yl) propanamide;
N - [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza- tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -6- (ethylamino) pyridine-2-carboxamide;
N - [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza- tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -6 - [(2-methoxyethyl) amino] -pyridine-2-carboxamide;
N- [10,11-Difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -benzamide;
3-Cyclopentyl- N- [10,11-Difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -propanamide;
2-Cyclohexyl- N- [10,11-Difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -acetamide;
N- [10,11-Dimethoxy-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -benzamide;
3-Cyclopentyl- N- [10,11-Dimethoxy-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -propanamide;
N- [9-Bromo-10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [ ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -benzamide;
3-Cyclopentyl- N- [12-oxo-11- (trifluoromethyl) -10,13,15-triazatetracyclo- [7.6.0.0 ^3.7 .0 ^10,14 ] Pentadec-1 (9), 2,7,14-tetraen-11-yl] -propanamide;
N- [10-chloro-4-oxo-3- (tri- fluoromethyl) -2,5,7-triaza- tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
N- [11-Chloro-4-oxo-3- (tri- fluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
3-Cyclopentyl- N- [9,10-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -propanamide;
3-Cyclopentyl- N- [9-methyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -propanamide;
3-Cyclopentyl- N- [9,10-Difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -propanamide;
3-Cyclopentyl- N- [9, 10-Di-chloro-4-oxo-3- (trifluoro-methyl) -2,5,7- triazatricyclo- [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -propanamide;
3-Cyclopentyl- N- [9, 11-di-chloro-4-oxo-3- (trifluoro-methyl) -2,5,7- triazatricyclo- [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -propanamide;
N- [9-chloro-4-oxo-3- (tri- fluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
3-Cyclopentyl- N- [9, 11-di-fluoro-4-oxo-3- (trifluoro-methyl) -2,5,7-triazatricyclo- [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -propanamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] oxane-4-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3- (1-hydroxycyclopentyl) propan-amide;
(2S) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -1-methane-sulfonylpyrrolidine-2-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6 - [(3-methoxypropyl) -amino] -pyridine-2-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6 - [(2-hydroxyethyl) amino] pyridine-2-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6 - {[(2S) -1- methoxypropan-2- yl] amino} pyridine- ;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6- {[2- (dimethylamino) -ethyl] amino-pyridine-2-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6 - [(2-methoxyethyl) (methyl) amino] -pyridine-2-carboxamide;
Methyl 6 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (8), 6,9,11-tetraen-3-yl] carbamoyl} pyridine-2-carboxylate;
2- N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6- N- (2-methoxyethyl) pyridine-2,6-dicarboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6- (hydroxymethyl) pyridine-2-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-fluorobenzamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3,5-difluorobenzamide;
3-cyano- N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (8), 6,9,11-tetraen-3-yl] benzamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2 - [(2-methoxyethyl) amino] -1,3-thiazole-4-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -1- (2,2-difluoroethyl) azetidine-3-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3-fluoroazetidine-3-carboxamide;
N- [10,11-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3- (3,3-difluoroazetidin-1-yl) -propanamide;
3- (3,3-Difluoroazetidin-1-yl) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -propanamide;
3-Cyclobutyl- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] propanamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3- (1-hydroxycyclopentyl) propanamide;
2-Cyclopentyl- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] acetamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3,5-difluorobenzamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6-fluoropyridine-2-carboxamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6 - [(2-methoxyethyl) amino] pyridine-2-carboxamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2-phenylacetamide;
2- (3,5-Dichlorophenyl) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] acetamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (3,4,5-trimethoxyphenyl) -propanamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3-methanesulfonylbenzamide;
3-Bromo-N- [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] benzamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3 - [(2-methoxyethyl) amino] benzamide;
2-Bromo-N- [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -1,3-thiazole-4-carboxamide;
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2 - [(2-methoxyethyl) amino] -1,3-thiazole-4-carboxamide;
N- [9-Bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentyl-propanamide;
N- [9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
N- [9-acetyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentyl-propanamide;
N- [10-Chloro-9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triaza- tricyclo [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
3-Cyclopentyl- N- [9-fluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N- [9,11-Dimethyl-4-oxo-3- (trifluoro-methyl) -2,5,7-triazatricyclo- [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N- [9-Chloro-10-fluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
N- [10-Chloro-9-methyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
3-Cyclopentyl- N- [4-oxo-3,9-bis (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] -Dodeca-1 (8), 6,9,11-tetraen-3-yl] propanamide;
N- [11-Bromo-4-oxo-3,9-bis- (trifluoromethyl) -2,5,7-triaza- tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -3-cyclopentylpropanamide;
N- [10-Chloro-9-fluoro-4-oxo-3- (trifluoromethyl) -2,5,7- triaza- tricyclo [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
3-Cyclopentyl- N- [9-fluoro-10-methoxy-4-oxo-3- (trifluoro-methyl) -2,5,7- triazatricyclo- [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N- [9- (Methyl-sulfanyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N- [9-methane-sulfonyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N- [9-Bromo-10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
N- [9,10-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6-fluoropyridine-2-carboxamide;
N- [9,10-Dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6 - [(2-methoxyethyl) amino] -pyridine-2-carboxamide;
N- [10-Chloro-9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triaza- tricyclo [ ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6-fluoropyridine-2-carboxamide;
N- [10-Chloro-9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triaza- tricyclo [ ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6 - [(2-methoxyethyl) amino] -pyridine-2-carboxamide;
N- [10-Chloro-9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triaza- tricyclo [ ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2 - [(2-methoxyethyl) amino] -1,3-thiazole-4-carboxamide;
N- [10-Chloro-9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triaza- tricyclo [ ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6 - {[(2S) -1- methoxypropan-2- yl] amino} pyridine- ;
N- [9,10-Difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6-fluoropyridine-2-carboxamide;
N- [9,10-Difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -6 - [(2-methoxyethyl) amino] -pyridine-2-carboxamide;
(2S) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triaza-tricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2-phenylpropanamide;
(2S) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2-phenyl-propanamide;
(2S) -3-cyclopentyl- N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2-methyl-propanamide;
(2S) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2-hydroxy-2-phenylacetamide;
(2S) - N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] -2-methoxy-2-phenylacetamide;
Methyl 3- (3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxylate;
3-Cyclopentyl- N - [9-iodo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-methoxypyridine-3-carboxamide;
N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-hydroxypyridine-3-carboxamide;
(2S) - N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-cyclohexylpropanamide;
(2S) -2- (Cyclopent-1-en-1-ylmethoxy) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N - [11-chloro-9-iodo-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] butanamide;
N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2- (cyclopentylamino) -1,3-thiazole-4-carboxamide;
3-Cyclopentyl- N - [9-Iodo-10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [9- (hydroxymethyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N - [9-butyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
3- (3-Cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxylic acid;
3-Cyclopentyl- N - {9- [1- (methoxyimino) ethyl] -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl} propanamide;
3- (3-Cyclopentylpropanamido) - N -Methyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxamide;
3-Cyclopentyl- N - [9-ethynyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [4-oxo-9- (trifluoromethoxy) -3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [9-cyclopropanesulfonamido-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3- (3-Cyclopentylpropanamido) - N -Methanesulfonyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxamide;
3-Cyclopentyl- N - [9-methanesulfonamido-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2 - [(2-methoxyethyl) amino] -1,3-thiazole-4-carboxamide;
N - [9-acetyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2 - [(2-methoxyethyl) amino] -1,3-thiazole-4-carboxamide;
3- (3,3-Difluoropyrrolidin-1-yl) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (3-fluoroazetidin-1-yl) propanamide;
3- (3,3-Difluoropiperidin-1-yl) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N - [9-acetyl-10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-methoxypyridine-3-carboxamide;
N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-hydroxypyridine-3-carboxamide;
N - [11-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
N - [10-bromo-9-fluoro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
N - [9-Bromo-10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
3-Cyclopentyl- N - [9-fluoro-10- (1 -hydroxyethyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N - [9-acetyl-10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
N - [9-Bromo- 11-chloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
N - [9-acetyl-11-chloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
N - [11-bromo-9-fluoro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
N - [11-acetyl-4-oxo-3,9-bis (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
N - [11-chloro-10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
3-Cyclopentyl- N - [9- (4-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N Pyrazol-4-yl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [9- (6-methoxypyridin-3-yl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [9- (3-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [9- (1,3-oxazol-2-yl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N - [9- (4- tert -butylphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
N - [9- (4-cyanophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
3-Cyclopentyl- N - [9- (4-nitrophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N - [9- (4-aminophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
3-Cyclopentyl- N - [4-oxo-9-phenyl-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [9- (2-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
2-hydroxy- N - [9- (4-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] pyridine-3-carboxamide;
3-Cyclopentyl- N - [9- (2-hydroxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [4-oxo-9- (1H-1,2,3,4-tetrazol-5-yl) -3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3- [3- (3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-9-yl] benzoic acid;
N - [9- (4-chlorophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
3-Cyclopentyl- N - [9- (4-methylphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [9- (3,4-dichlorophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [9- (3,4- dihydro-2H-pyran-5-yl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N Pyrazol-4-yl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [ 6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [10,11-dimethyl-4-oxo-9- (1,2-thiazol-4-yl) -3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4. 0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [9- (furan-3-yl) -10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N - [9- (4-methoxyphenyl) -10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] acetamide;
3-Cyclopentyl- N - [9-fluoro-10- (4-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [11- (4- methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
(2S) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2- (3-methylbutoxy) propanamide;
(2R) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2- (3-methylbutoxy) propanamide;
(2R) -2- (3-chlorophenoxy) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
(2S) - N - [9-acetyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-cyclohexylpropanamide;
(2S) -3-cyclopentyl- N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-hydroxypropanamide;
(2S) -2- (Cyclopentylmethoxy) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclohexyl- N - [4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -6 - [(2-methoxyethyl) amino] pyridine-2-carboxamide;
N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3- (1-hydroxycyclopentyl) propanamide;
3-Cyclopentyl- N - [9-methanesulfonyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [9,10-difluoro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N - [9-acetyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 6] dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
3- (3,3-Difluoroazetidin-1-yl) - N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N - [9-cyano-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
3-Cyclopentyl- N - [9- (2-methylpropanoyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-phenylpropanamide;
3,5-Dichloro- N - [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] benzamide;
3-Cyclopentyl- N - [9- (4-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3- (3-Cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxylic acid;
3-Cyclopentyl- N - {9- [4- (methylsulfanyl) phenyl] -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl} propanamide;
(3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxylic acid;
N - [9- (4-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] butanamide;
2 - [(2-methoxyethyl) amino] - N - [9- (4-methoxyphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -1,3-thiazole-4-carboxamide;
N - [9-bromo-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2-hydroxy-1,3-thiazole-4-carboxamide;
N - [10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2 - [(2-methylpropyl) amino] -1,3-thiazole-4-carboxamide;
3-Cyclopentyl- N - {9- [4- (dimethylamino) phenyl] -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl} propanamide;
N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2,2,2-trifluoroacetamide;
N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2- (2-methoxyethoxy) pyridine-4-carboxamide;
3-Cyclopentyl- N - [9- (4- methanesulfonylphenyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2,2-dimethylpropanamide;
N - [9-acetyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2- (cyclopentylamino) -1,3-thiazole-4-carboxamide;
N - [9- (3-chlorophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -3-cyclopentylpropanamide;
3-Cyclopentyl- N - [4- oxo-3- (trifluoromethyl) -9- [4- (trifluoromethyl) phenyl] -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3-Cyclopentyl- N - [9- (4-fluorophenyl) -4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
3- (3-Cyclopentylpropanamido) - N -Methanesulfonyl-10-methoxy-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraene-9-carboxamide;
3-Cyclopentyl- N - [9- (methoxymethyl) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] propanamide;
tert -Butyl 3 - {[10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] carbamoyl} pyrrolidine-1-carboxylate;
tert -Butyl 4- {[10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] carbamoyl} piperidine-1-carboxylate;
tert -Butyl (2S) -2 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] carbamoyl} pyrrolidine-1-carboxylate;
tert -Butyl 3 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] carbamoyl} pyrrolidine-1-carboxylate;
tert -Butyl 4 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] carbamoyl} piperidine-1-carboxylate;
tert -Butyl 3 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] carbamoyl} azetidine-1-carboxylate;
tert -Butyl 4 - ({[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [ ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] carbamoyl} methyl) piperidine-1-carboxylate;
tert -Butyl 2- (2- {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo- [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] carbamoyl} ethyl) piperidine-1-carboxylate;
tert- Butyl 3 - {[10,11-dichloro-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (8), 6,9,11-tetraen-3-yl] carbamoyl} -3-fluoroazetidine-1-carboxylate;
Methyl 3- [3- (3-cyclopentylpropanamido) -4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-9-yl] benzoate;
N - [10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] acetamide;
N - [9-bromo-10,11-dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7- triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] acetamide; And
N- [10,11-Dimethyl-4-oxo-3- (trifluoromethyl) -2,5,7-triazatricyclo [6.4.0.0 ^2,6 ] Dodeca-1 (12), 6,8,10-tetraen-3-yl] -2 - [(2-methoxyethyl) amino] pyrimidine-4-carboxamide. 12. A compound according to any one of claims 1 to 11, for use in therapy, or a pharmaceutically acceptable salt thereof. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 12. A compound according to any one of claims 1 to 11 for use in the treatment of cancer, inflammatory disorders, autoimmune disorders or neurodegenerative disorders. Cancer, inflammatory disorder, autoimmune disorder or neurodegenerative disorder,
12. A method of treatment comprising administering a compound according to any one of claims 1 to 11 to a mammal in need of such treatment.

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